Coumarin compounds as receptor modulators with therapeutic utility

ABSTRACT

The present invention relates to novel 2-oxo-2H-chromene-3-carboxamide derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser. No. 61/254,236 filed on Oct. 23, 2009, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel 2-oxo-2H-chromene-3-carboxamide derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with sphingosine-1-phosphate 1 (S1P1) receptor modulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases. On the other hand the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers. These are currently topics that are attracting great interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1-phosphate metabolism is under active investigation.

International patent application WO2008/092930 A1 discloses Chromene S1P1 receptor antagonists.

International patent application WO2007/115820 A1 discloses Chromen-2-one derivatives.

United States Patent Application Publication US2006/0148834 A1 discloses coumarin derivatives, their carboxamides, pharmaceutical compositions containing them and their uses.

SUMMARY OF THE INVENTION

We have now discovered a group of novel compounds which are potent and selective sphingosine-1-phosphate modulators. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of sphingosine-1-phosphate receptors. The term “modulator” as used herein, includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.

This document describes compounds of Formula I, which have sphingosine-1-phosphate receptor biological activity. The compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by S1P modulation, and in particular use as S1P1 agonists or antagonists (functional antagonists).

In one aspect the invention provides a compound having Formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, and the geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:

wherein:

R¹ is hydrogen, halogen or C₁₋₆alkyl;

R² is CR³ or N;

R³ is hydrogen, halogen, O(C₁₋₆alkyl), S(C₁₋₆alkyl), cyano, aldehyde, heterocycle, C₁₋₆alkyl or hydroxyl;

R⁴ is CR⁵ or N;

R⁵ is hydrogen, halogen, hydroxyl or non-substituted C₁₋₆alkyl;

R⁶ is CR⁷ or N;

R⁷ is —NHR¹², —S(O)₂R¹⁴, —C(O)NHR¹⁶, —OR¹⁷, hydrogen, halogen, phosphonic acid, boronic acid, —CH₂—OH, —CH₂—S(O)₂CH₃, —(CH₂)_(a)—NH—(CH₂)_(b)—O_(c)—P(O)(OH)₂, —(CH₂)_(d)—C(NH₂)(CH₂OH)(CH₂—O—P(O)(OH)₂), —(CH₂)_(e)—C(NH₂)(CH₃)(CH₂—O—P(O)(OH)₂); or —(CH₂)_(f)—NH—(CH₂)_(g)—SO₃H;

a is 1 or 2;

b is 2 or 3;

c is 0 or 1;

d is 0 or 1;

e is 0 or 1;

f is 0 or 1;

g is 2 or 3;

R⁸ is CR⁹ or N;

R⁹ is hydrogen, halogen, non-substituted C₁₋₆alkyl or hydroxyl;

R¹⁰ is CR¹¹ or N;

R¹¹ is hydrogen, halogen or C₁₋₆alkyl;

R¹² is hydrogen, C₁₋₆alkyl, —C(O)R¹³, —S(O)₂(C₁₋₃alkyl) or heterocycle;

R¹³ is amino or C₁₋₆alkyl;

R¹⁴ is C₁₋₄alkyl, NHR¹⁵ or hydroxyl;

R¹⁵ is hydrogen or C₁₋₆alkyl;

R¹⁶ is hydrogen or C₁₋₆alkyl;

R¹⁷ is hydrogen, C₁₋₆alkyl or —S(O)₂(C₁₋₃alkyl);

R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl;

R¹⁹ is hydrogen, halogen or C₁₋₆alkyl;

R²⁰ is hydrogen, halogen or C₁₋₆alkyl; and

R²¹ is —OC₁₋₄alkyl.

The term “alkyl”, as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1-8 carbon atoms, preferably 1-6 carbon atoms and more preferable 1-4 carbon atoms. One methylene (—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent (C₃₋₆cycloalkyl). Alkyl moieties can optionally be substituted by halogen, hydroxyl, cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid, phosphonic acid groups, sulphonic acid groups, phosphoric acid. Usually, in the present case, alkyl groups are methyl, ethyl, iso-propyl, 1-methylsulfanyl, trifluoromethyl, methylsulfanyl, isopropyldifluoro, n-propyl, propylsulphonic acid, 1,1,1,2,2 pentafluoroethyl, 3(ethylamino)cyclobutylphosphonic acid. Preferred alkyl groups are methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl.

The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, preferably 3-6 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl can be optionally substituted by C₁₋₃ alkyl groups or halogen. Usually, in the present case, cycloalkyl groups are cyclohexyl, methylcyclopropyl, cyclobutyl.

The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine. Usually, in the present case, halogens are chlorine, fluorine, bromine.

The term “heterocycle” as used herein, refers to a 3 to 10 membered ring, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof interrupting the carbocyclic ring structure. The heterocyclic ring can be saturated or non-saturated. The heterocyclic ring can be interrupted by a C═O, the S heteroatom can be oxidized. Heterocyclic ring moieties can optionally be substituted by hydroxyl, C₁₋₃alkyl or halogen. Usually heterocyclic groups in the present case are piperidyl, pyrryl, furyl.

The term “aryl” as used herein, is defined as including an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen, which can optionally be substituted by 1 to 3 halogen atoms or by 1 to 2 C₁₋₃alkyl groups. Usually aryl is phenyl.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula “—C═O”.

The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “aldehyde” as used herein, represents a group of formula “—C(O)H”.

The term “sulfonyl” as used herein, represents a group of formula “—SO₂”.

The term “sulfate” as used herein, represents a group of formula “—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula “—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula “—(O)P(O)(OH)₂”.

The term “boronic acid”, as used herein, represents a group of formula “—B(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula “—S(O)₂OH”.

The term “modulator” as used herein, represents receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.

Generally R¹ is hydrogen, halogen, C₁₋₆alkyl. Usually R¹ is hydrogen.

Generally R² is CR³ or N. Usually R² is CR³.

Generally R³ is hydrogen, halogen, O(C₁₋₆alkyl), S(C₁₋₆alkyl), cyano, aldehyde, heterocycle, C₁₋₆alkyl or hydroxyl. Usually R³ is hydrogen, CF₃, Br, Cl, OMe, Me, OCHF₂, OCF₃, SMe, furyl, —C(O)H, Ethyl, cyano or n-Propyl.

Generally R⁴ is CR⁵ or N.

Generally R⁵ is hydrogen, halogen, non-substituted C₁₋₆alkyl or hydroxyl. Usually R⁵ is hydrogen, fluoro or methyl.

Generally R⁶ is CR⁷ or N.

Generally R⁷ is —NHR¹², —S(O)₂R¹⁴, —C(O)NHR¹⁶, —OR¹⁷, hydrogen, halogen, phosponic acid, boronic acid, —CH₂—OH, —CH₂—S(O)₂CH₃, —(CH₂)_(a)—NH—(CH₂)_(b)—O_(c)—P(O)(OH)₂, —(CH₂)_(d)—C(NH₂)(CH₂OH)(CH₂—O—P(O)(OH)₂), —(CH₂)_(e)—C(NH₂)(CH₃)(CH₂—O—P(O)(OH)₂) or (CH₂)_(f)—NH—(CH₂)_(g)—SO₃H.

Usually R⁷ is —NH—S(O)₂CH₃, hydrogen, —S(O)₂NH₂, hydroxyl, C(O)NH₂, CH₂OH, CH₂—S(O)₂CH₃, phosponic acid or boronic acid.

Generally a is 1 or 2.

Generally b is 2 or 3.

Generally c is 0 or 1.

Generally d is 0 or 1.

Generally e is 0 or 1.

Generally f is 0 or 1.

Generally g is 2 or 3.

Generally R⁸ is CR⁹ or N.

Generally R⁹ is hydrogen, halogen, non-substituted C₁₋₆alkyl or phosponic acid, boronic acid. Usually R⁹ is hydrogen, fluoro or methyl.

Generally R¹⁰ is CR¹¹ or N.

Generally R¹¹ is hydrogen, halogen or C₁₋₆alkyl. Usually R¹¹ is hydrogen, chloro or methyl.

Generally R¹² is hydrogen, C₁₋₆alkyl, —C(O)R¹³, —S(O)₂(C₁₋₃alkyl), heterocycle. Usually R¹² is hydrogen, S(O)₂(methyl), —C(O)CH(NH₂)CH₂—COOH, C(O)CH₃, pyroyl or piperidinyl.

Generally R¹³ is amino, C₁₋₆alkyl. Usually R¹³ is amino, methyl, —CH(NH₂)CH₂COOH.

Generally R¹⁴ is C₁₋₄alkyl, —NHR¹⁵ or hydroxyl. Usually R¹⁴ is amino, —NH(CH₂)₂COOH.

Generally R¹⁵ is hydrogen, C₁₋₆alkyl. Usually R¹⁵ is H, methyl, —CH₂-heterocycle, —(CH₂)₂—COOH or —CH₂—P(O)(OH)₂.

Generally R¹⁶ is hydrogen or C₁₋₆alkyl. Usually R¹⁶ is hydrogen,

Generally R¹⁷ is hydrogen, C₁₋₆alkyl or —S(O)₂(C₁₋₃alky). Usually R¹⁷ is hydrogen, —S(O)₂CH₃.

Generally R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl. Usually R¹⁸ is methyl, n-propyl, O-ethyl or O-isopropyl.

Generally R¹⁹ is hydrogen, halogen or C₁₋₆alkyl. Usually R¹⁹ is hydrogen.

Generally R²⁰ is hydrogen, halogen or C₁₋₆alkyl. Usually R²⁰ is hydrogen.

Generally R²¹ is —OC₁₋₄alkyl. Usually R²¹ is O-methyl or O-ethyl.

In one embodiment of the invention

R¹ is hydrogen; and

R² is CR³; and

R³ is halogen, O(C₁₋₆alkyl), S(C₁₋₆alkyl), cyano, aldehyde, heterocycle, C₁₋₆alkyl; and

R⁴ is CR⁵ or N; and

R⁵ is hydrogen or halogen; and

R⁶ is CR⁷ or N; and

R⁷ is —NHR¹², —S(O)₂R¹⁴, —OR¹⁷, hydrogen, phosphonic acid, boronic acid, —CH₂—OH, —CH₂—S(O)₂CH₃; and

R⁸ is CR⁹ or N; and

R⁹ is hydrogen, halogen or non-substituted C₁₋₆alkyl; and

R¹⁰ is CR¹¹; and

R¹¹ is hydrogen, halogen or C₁₋₆alkyl; and

R¹² is —S(O)₂(C₁₋₃alkyl), C(O)R¹³ or heterocycle; and

R¹³ is C₁₋₆alkyl; and

R¹⁴ is NHR¹⁵; and

R¹⁵ is hydrogen or C₁₋₆alkyl; and

R¹⁶ is C₁₋₆alkyl; and

R¹⁷ is hydrogen, or —S(O)₂(C₁₋₃alkyl); and

R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl; and

R¹⁹ is hydrogen; and

R²⁰ is hydrogen; and

R²¹ is —OC₁₋₄alkyl.

In another embodiment of the invention

R¹ is hydrogen; and

R² is CR³; and

R³ is halogen, O(C₁₋₆alkyl), C₁₋₆alkyl; and

R⁴ is CR⁵ or N; and

R⁵ is hydrogen; and

R⁶ is CR⁷ or N; and

R⁷ is —NHR¹², —S(O)₂R¹⁴, —OR¹⁷, hydrogen, phosphonic acid or boronic acid; and

R⁸ is CR⁹; and

R⁹ is hydrogen; and

R¹⁰ is CR¹¹; and

R¹¹ is hydrogen or C₁₋₆alkyl; and

R¹² is —S(O)₂(C₁₋₃alkyl) or C(O)R¹³; and

R¹³ is C₁₋₆ alkyl; and

R¹⁴ is NHR¹⁵; and

R¹⁵ is hydrogen; and

R¹⁷ is hydrogen; and

R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl; and

R¹⁹ is hydrogen; and

R²⁰ is hydrogen; and

R²¹ is —OC₁₋₄alkyl.

Compounds of the invention are:

N-[4-(hydroxymethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(4-amino-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(acetylamino)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

3-{[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)sulfonyl]amino}propanoic acid;

N-(2-chlorophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-N-[4-(piperidin-3-ylamino)phenyl]-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-[4-(pyrrolidin-3-ylamino)phenyl]-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-N-{4-[(piperidin-2-ylmethyl)amino]phenyl}-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-N-{4-[(piperidin-3-ylmethyl)amino]phenyl}-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methylphenyl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-cyanophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-4-[(methylamino)sulfonyl]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-[2-(methylthio)phenyl]-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethoxy)phenyl]-2H-chromene-3-carboxamide;

N-[2-(2-furyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(3-fluoro-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-fluorophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-ethylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methoxyphenyl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide;

N-(2-bromophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl methanesulfonate;

N-[2-(difluoromethoxy)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(3-bromopyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(3-chloropyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-chloro-5-methylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-(2-propylphenyl)-2H-chromene-3-carboxamide;

N-(6-amino-2-methylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl- 2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-pyridin-4-yl-2H-chromene-3-carboxamide;

7-methoxy-N-(3-methylpyridin-4-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-[3-(trifluoromethyl)pyridin-4-yl]-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-pyridin-3-yl-2H-chromene-3-carboxamide;

N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide;

7-methoxy-N-(3-methylpyridin-2-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-formylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(3-chloropyridazin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(3-chloro-4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}phenyl)boronic acid;

N-(2-chloro-5-fluoropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)phosphonic acid;

N-[4-(aminosulfonyl)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid;

8-isopropoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide;

8-isopropoxy-7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-2H-chromene-3-carboxamide;

8-ethoxy-7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-2H-chromene-3-carboxamide;

8-ethoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide;

8-ethoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide;

8-isopropoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-4-[(methylsulfonyl)methyl]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-{2-chloro-4-[(methylsulfonyl)amino]phenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid;

N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-8-ethoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-8-isopropoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide;

7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-8-ethyl-7-methoxy-2-oxo-2H-chromene-3-carboxamide.

Preferred compounds of the invention are:

7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide;

N-(3-bromopyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-bromophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-[3-(trifluoromethyl)pyridin-4-yl]-2H-chromene-3-carboxamide;

N-(3-chloropyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

8-ethoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide;

N-(2-ethylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)phosphonic acid;

(3-chloro-4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}phenyl)boronic acid;

7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethoxy)phenyl]-2H-chromene-3-carboxamide;

N-[2-(difluoromethoxy)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-8-isopropoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-8-ethoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(acetylamino)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide;

N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid;

N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid;

N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide.

Most preferred compounds of the invention are:

7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide;

N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide;

7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid;

N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

(4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid;

N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide;

N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide.

Some compounds of Formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic, for example, a hydrohalic such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.

Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

The compounds of the invention are indicated for use in treating or preventing conditions in which there is likely to be a component involving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier.

In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.

These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1P1 modulation: not limited to the treatment of diabetic retinopathy, other retinal degenerative conditions, dry eye, angiogenesis and wounds.

Therapeutic utilities of S1P1 agonists are ocular disease, such as but not limited to: wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases such as but not limited to: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression such as but not limited to: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, autoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases such as but not limited to: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection such as but not limited to: ischemia reperfusion injury and atherosclerosis; or wound healing such as but not limited to: scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation such as but not limited to: treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity such as but not limited to: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains.

In still another embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof.

The present invention concerns the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases, various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression, rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, autoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases, urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection, ischemia reperfusion injury and atherosclerosis; or wound healing, scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains.

The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.

The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier therefor. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.

Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.

Invention compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.

Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of sphingosine-1-phosphate receptors. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of sphingosine-1-phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term “therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.

The present invention concerns also processes for preparing the compounds of Formula I.

The compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.

The synthetic scheme set forth below, illustrates how compounds according to the invention can be made. Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I.

General schemes for synthesizing coumarin derivatives:

Substituted 2H-chromene-3-carboxylic acids intermediates, prepared from known procedures, and the desired aniline in N,N-dimethylformamide were treated with o-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and diisopropylethyl amine. The reaction was stirred at room temperature for 16 hours. The solution was quenched with water and the product extracted with ethylacetate. The organic layers were combined and dried over sodium sulfate. The organic layer was filtered and evaporated under vacuum to afford the crude amide. Purification via medium pressure liquid chromatography (gradient MeOH/DCM) afforded the desired compound the corresponding compound of Formula I.

To the substituted-2H-chromene-3-carboxylic acids intermediates, prepared from known procedures, in dichloromethane are added diisopropyl ethyl amine and a 50% solution of propylphosphonic anhydride in ethyl acetate. The mixture was stirred for 30 minutes at room temperature. The desired aniline is added to the reaction mixture which is stirred at room temperature overnight. The reaction mixture is then poured onto ice water and dichloromethane is added. The organic layer is separated and washed with brine dried with sodium sulfate, filtered and concentrated to dryness. The residue was triturated with dichloromethane/Hexanes and then the solid was passed through a medium pressure liquid chromatography to give the corresponding compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.

It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.

The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium ²H (or D) in place of protium ¹H (or H) or use of ¹³ C enriched material in place of ¹²C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.

The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.

The IUPAC names of the compounds mentioned in the examples were generated with ACD version 8.

Unless specified otherwise in the examples, characterization of the compounds is performed according to the following methods:

NMR spectra are recorded on 300 or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal trimethylsilyl or to the residual solvent signal.

All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Ryan Scientific, Syn Chem, Chem-Impex, Aces Pharma, however some known intermediates, for which the CAS registry number [CAS #] are mentioned, were prepared in-house following known procedures.

Usually the compounds of the invention were purified by flash column chromatography using a gradient solvent system of methanol/dichloromethane unless otherwise reported.

The following abbreviations are used in the examples:

NH₃ ammonia

BOC tert-butyloxy carbonyl

CH₃CN acetonitrile

PPPA propylphosphonic anhydride

PSI pound per square inch

ClSO₂OH chlorosulfonic acid

DIPEA diisopropylethyl amine

DCM dichloromethane

DMF N,N-dimethylformamide

HATU o-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

NaOH sodium hydroxide

MeOH methanol

CD₃OD deuterated methanol

NH₃ ammonia

HCl hydrochloric acid

NaIO₄ sodium periodate

Na₂SO₄ sodium sulfate

ON overnight

R.T. room temperature

MgSO₄ magnesium sulfate

EtOAc ethyl acetate

CDCl₃ deuterated chloroform

DMSO-d₆ deuterated dimethyl sulfoxide

MPLC medium pressure liquid chromatography

TFA trifluoroacetic acid

THF tetrahydrofuran

PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II) chloride

LiCl lithium chloride

Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium

CH₃CN acetonitrile

TEA triethylamine

EDTA ethylenediaminetetraacetic acid

BCl₃ boron trichloride

NaHCO₃ sodium bicarbonate

TBME tert-butyl methylether

CH₃CHO acetaldehyde

Hantzsch ester diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

The following synthetic schemes illustrate how compounds according to the invention can be made. Those skilled in the art will be routinely able to modify and/or adapt the following schemes to synthesize any compound of the invention covered by Formula I.

Some compounds of this invention can generally be prepared in one step from commercially available literature starting materials.

EXAMPLE 1 Compound 1 N-(3-Fluoro-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide

7-Methoxy-2-oxo-8-propyl-2H-chromene-3-carboxylic acid (CAS 952504-50-6) (Intermediate 1) (0.20 g, 0.76 mmol) and 3-fluoro-2-methyl-phenylamine [CAS 443-86-7] (0.09 mL, 0.84 mmol) in DMF (20 mL) were treated with HATU (0.42 g, 1.1 mmol) and diisopropylethyl amine (0.38 mL, 2.3 mmol). The reaction was stirred at r.t. for 16 hours. The solution was quenched with water and the product extracted with EtOAc. The organic layers were combined and dried over Na₂SO₄. The organic layer was filtered and evaporated under vacuum to afford the crude title compound. Purification via MPLC (gradient MeOH/DCM) afforded 0.14 g (50%) of Compound 1.

¹H NMR (600 MHz, CDCl₃-d₃) δ 10.92 (s, 1H), 8.95 (s, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.25-7.17 (m, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.87 (t, J=8.7 Hz, 1H), 3.98 (s, 3H), 2.93-2.78 (m, 2H), 2.34 (d, J=1.3 Hz, 3H), 1.67-1.60 (m, 2H), 1.00 (t, J=7.3 Hz, 3H).

EXAMPLE 2 Intermediate 2 8-Ethyl-7-methoxy-2-oxo-2H-chromene-3-carboxylic acid

Step 1: 1,3-Cyclohexanedione (10 g, 89.2 mmol), 40% aqueous CH₃CHO (49.4 g, 445.9 mmol) were dissolved in methanol (40 mL) followed by addition of Hantzsch ester (22.7 g, 89.2 mmol) and pyridine (2.1 g, 18.74 mmol) under nitrogen. The resulting light yellow mixture was stirred at room temperature overnight, then concentrated to give crude product that was re-slurried in a mixture of CH₂Cl₂ (40 mL) and hexanes (60 mL) to furnish 2-ethyl-1,3-cyclohexanedione (8.6 g, 69%).

Step 2: 2-Ethyl-1,3-cyclohexanedione (15 g, 107 mmol), mesitylene (240 mL), and 5% Pd/C (7.8 g) were placed in a flask. The reaction mixture was stirred at 160° C. for two days. Filtration gave a crude product, which was purified by chromatography (EtOAc/Hexane) to give 2-ethyl-3-hydroxy phenol (2.2 g, 15%).

Step 3: DMF (46 mL) was placed in a flask followed by addition of POCl₃ (30.2 g, 194.34 mmol) dropwise at 0° C. The mixture was stirred at −5° C. for 30 min followed by addition of a solution of 2-ethyl-3-hydroxy phenol (8.95 g, 64.78 mmol) in DMF (40 mL). After 3.5 hours, the reaction mixture was poured into 2M aq. NaOH, and extracted with EtOAc (2×200 mL). The remained aqueous solution was neutralized with 5M aq. HCl. to pH ˜5, extracted with EtOAc (2×200 mL), and the EtOAc phase was dried over Na₂SO₄, concentrated, purified by chromatography (EtOAc/Hexane) to give a desired product (11 g, 62%).

Step 4: Sodium hydride (60%, 2.8 g) was added portionwise to a solution of 2-ethyl-3,4-dihydroxybenzaldehyde (5.8 g, 34.93 mmol) in DMSO (80 mL) at −10° C. under nitrogen, and the resulting mixture was stirred at −10° C. for 1.5 hours followed by addition of iodomethane (4.96 g, 34.93 mmol) dropwise. The solution was warmed to room temperature, and stirred overnight. The reaction solution was poured into ice/water, extracted with TBME. The combined organic phase was dried over anhydrous Na₂SO₄, and concentrated to give a crude product that was purified by chromatography to give 2-hydroxy-4-methoxy-3-ethyl-benzaldehyde (3.75 g, 55%).

Step 5: To a solution of 2-hydroxy-4-methoxy-3-ethyl-benzaldehyde (3.1 g, 17.2 mmol) in ethanol (93 mL) is added diethyl malonate (2.8 g, 17.2 mmol) and piperidine (1.5 g, 17.2 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then cooled to 0° C. with ice/water bath and the formed precipitate was filtered and washed with ethanol to give 7-methoxy-2-oxo-8-ethyl-2H-chromene-3-carboxylic acid ethyl ester (3.1 g, 65%).

Step 6: To a solution of 7-methoxy-2-oxo-8-ethyl-2H-chromene-3-carboxylic acid ethyl ester (3.1 g, 11.2 mmol) in THF (62 mL) was added at 0° C. a 1M solution of NaOH (25 mL). The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. with ice/water bath and pH was adjusted to ˜1 by adding 1M HCl solution. The formed precipitate was filtered and washed with water, dried to give the title Intermediate 2 (2.55 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.95 (br s, 1H), 8.69 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 3.93 (s, 3H), 2.71 (q, J=7.3 Hz, 2H), 1.08 (t, J=7.3 Hz, 3H).

EXAMPLE 3 Intermediate 3 7,8-Diethoxy-2-oxo-2H-chromene-3-carboxylic acid

Step 1: Sodium hydride (60%, 64 g) was added portionwise to a solution of 2,3,4-trihydroxybenzaldehyde (61.6 g, 400 mmol) at −10° C. under nitrogen, and the resulting mixture was stirred at −10° C. for 1.5 hours followed by addition of iodoethane (206 g, 1.32 mol) dropwise. The solution was warmed to room temperature, and stirred overnight. The reaction solution was poured into ice/water (3.5 kg), extracted with TBME (500 mL×5). The combined organic phase was washed with sat. NaHCO₃ (400 mL×3) and water (400 mL×2), dried over anhydrous Na₂SO₄, and concentrated to give a crude product (50 g) that was used directly for the next step without further purification.

Step 2: A solution of crude 2,3,4-triethoxybenzaldehyde (50 g) from step 1 was dissolved in CH₂Cl₂ followed by slow addition of 1M BCl₃ in CH₂Cl₂ (188 mL) while controlling the temperature at about 25° C. The resulting mixture was stirred at room temperature for 2 hours and then carefully poured into sat. aq. NaHCO₃. The solution was adjusted to pH ˜1 by addition of concentrated HCl. The organic phase was separated, and the aqueous phase was extracted with TBME. The combined organic phase was dried over anhydrous Na₂SO₄, concentrated to give a crude product that was purified by chromatography to furnish the desired product (9.8 g, 21%).

Step 3: The material from Step 2 (11.2 g, 53.3 mmol) and diethyl malonate (8.54 g, 53.3 mmol) were dissolved in anhydrous ethanol (310 mL) under nitrogen. The mixture was cooled with ice/water followed by addition of piperidine (4.54 g, 53.3 mmol), and stirred at room temperature for 2 hours. The reaction solution was stored at −20° C. for 3 hours. Filtration gave a crude solid that was washed with cooled ethanol, and then dissolved in CH₂Cl₂, dried over anhydrous Na₂SO₄, concentrated to give a crude product that was purified by chromatography (EtOAc/Hexane) to obtain a desired product (14.0 g, 85.9%).

Step 4: The material from Step 3 (14.0 g, 45.7 mmol) was dissolved in THF (280 mL), cooled with ice/water followed by addition of 1M aq. NaOH (220 mL), and stirred at room temperature overnight. The organic phase was separated, and the aqueous phase was extracted with TBME (100 mL×3). The aqueous phase was adjusted to pH ˜1 by 1M aq. HCl, and then added CH₂Cl₂. The CH₂Cl₂ phase was separated and the aqueous phase was extracted with CH₂Cl₂. The combined CH₂Cl₂ was dried over anhydrous Na₂SO₄, and concentrated to give a light yellow solid as the title compound (12 g, 94.5%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.98 (s, 1H), 8.66 (s, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.07 (q, J=7.0 Hz, 2H), 1.37 (t, J=6.9 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H).

EXAMPLE 4 Intermediate 4 8-Isopropoxy-7-methoxy-2-oxo-2H-chromene-3-carboxylic acid

Step 1: A solution of 2,3,4-trimethoxybenzaldehyde (9.81 g, 50 mmol) was dissolved in CH₂Cl₂ (250 mL) followed by addition of BCl₃ solution (1M, in CH₂Cl₂, 50 mL) dropwise. The mixture was stirred at room temperature for 2 hours, and then added another equivalent of BCl₃ solution (1M in CH₂Cl₂, 50 mL). The reaction mixture was stirred at RT overnight, and poured into 10% NaHCO₃. The aqueous layer was acidified by 2M H₂SO₄ to pH ˜1, extracted with EtOAc, dried over Na₂SO₄, concentrated to give a grey product (7.4 g, 88%).

Step 2: The compound from the previous step (20 g, 118.94 mmol) was added to a solution of sodium hydride (60%, 11 g) in dry DMSO (300 mL). The mixture was stirred for 40 min, added potassium iodide (20.0 g, 120.5 mmol) and stirred another 10 minutes followed by addition of 2-bromopropane (15.0 g, 122 mmol). The mixture was stirred overnight, diluted with EtOAc. The organic phase was dried over Na₂SO₄ and concentrated to give a crude product that was purified by chromatography (EtOAc/Hexane) to give a desired product (5.4 g, 21%).

Step 3: The compound from the previous step (10.8 g, 51.37 mmol) and diethyl malonate (8.9 g, 55.57 mmol) were dissolved in anhydrous ethanol (300 mL) under nitrogen. The mixture was cooled with ice/water followed by addition of piperidine (4.7 g, 55.20 mmol), and stirred at room temperature for 2 hours. The reaction solution was stored at −20° C. for 3 hours. Filtration gave a crude solid that was washed with cooled ethanol, dried to obtain a desired product (10.4 g, 65%).

Step 4: The material from the previous step (8.3 g, 27.1 mmol) was dissolved in THF (100 mL), cooled with ice/water followed by addition of 1M aq. NaOH (50 mL), and stirred at room temperature overnight. The organic phase was separated, and the aqueous phase was extracted with TBME (50 mL×2). The remained aqueous phase was adjusted to pH ˜1 by 1M aq. HCl, and then cooled to 0° C. Filtration and drying gave a light yellow title intermediate (7 g, 25.16 mmol, 93.2%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.98 (br s, 1H), 8.68 (s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 4.50-4.34 (m, 1H), 3.91 (s, 3H), 1.24 (d, J=6.2 Hz, 6H).

EXAMPLE 5 Intermediate 5 8-Ethoxy-7-methoxy-2-oxo-2H-chromene-3-carboxylic acid

Step 1: A solution of 2,3,4-trimethoxybenzaldehyde (9.81 g, 50 mmol) was dissolved in CH₂Cl₂ (250 mL) followed by addition of BCl₃ solution (1M, in CH₂Cl₂, 50 mL) dropwise. The mixture was stirred at room temperature for 2 hours, and then added another equivalent of BCl₃ solution (1M in CH₂Cl₂, 50 mL). The reaction mixture was stirred at room temperature overnight, and poured into 10% NaHCO₃. The aqueous layer was acidified by 2M H₂SO₄ to pH ˜1, extracted with EtOAc, dried over Na₂SO₄, concentrated to give a grey product (7.4 g, 88%).

Step 2: The product from the previous step (10.0 g, 59.47 mmol) was added to a solution of sodium hydride (4.8 g, 60%, 120 mmol) in dry DMSO (200 mL). The mixture was stirred for 20 min and iodoethane (9.4 g, 60.27 mmol) was added then stirred overnight. The reaction was quenched with water, adjusted by con. HCl to pH ˜6, extracted with EtOAc. The organic phase was washed with H₂O and sat. aq. NaCl, dried, and concentrated to give a brown oil product (12 g, 55%).

Step 3: The product from the previous step (10.8 g, 55 mmol) and diethyl malonate (8.9 g, 55.6 mmol) were dissolved in anhydrous ethanol (300 mL) under nitrogen. The mixture was cooled with ice/water followed by addition of piperidine (4.7 g, 55.2 mmol), and stirred at room temperature for 2 hours. The reaction solution was stored at −20° C. for 3 hours. Filtration gave a crude solid that was washed with cooled ethanol, dried to obtain a desired product (10.4 g, 35.6 mmol, 65%).

Step 4: The product from the previous step (15.0 g, 51.32 mmol) was dissolved in THF (300 mL), cooled with ice/water followed by addition of 1M aq. NaOH (150 mL), and stirred at room temperature overnight. The organic phase was separated, and the aqueous phase was extracted with TBME (100 mL×3). The remained aqueous phase was adjusted to pH ˜1 by 1M aq. HCl, and cooled to 0° C. Filtration and drying gave a light yellow title compound (13.2 g, 49.96 mmol, 97.5%).

¹H NMR (300 MHz, DMSO-d₆) δ 13.00 (br s, 1H), 8.68 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.17 (d, J=9.1 Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.92 (s, 3H), 1.28 (t, J=7.0 Hz, 3H).

Compounds 2-16, 18-20, 22-24, 26-40, 43-45, 47, 48, 51, 54, 56, 57, 58, 59, 60, 61, 64, 65, 62, 63, 69, 70, 71 and 72 were prepared from Intermediate 1 (unless otherwise specified) and the corresponding amine, in a similar manner to the method described in Example 1 for Compound 1. The reagents used and the results are described below in Table 1.

TABLE 1 Compound number IUPAC name Reagent(s) used ¹H NMR δ (ppm) for Compound 2 N-(2- 2-fluoro- (600 MHz; CDCl₃) δ 11.18 (br s, fluorophenyl)- phenylamine 1H), 8.92 (s, 1H), 8.50 (td, J = 1.5, 7-methoxy-2- [CAS 348-54-9] 8.0 Hz, 1H), 7.57 (d, J = 8.7 Hz, oxo-8-propyl- 1H), 7.20-7.13 (m, 2H), 2H-chromene- 7.12-7.08 (m, 1H), 6.97 (d, J = 8.8 Hz, 3-carboxamide 1H), 3.98 (s, 3H), 2.87 (dd, J = 7.0, 8.4 Hz, 2H), 1.63 (sxt, J = 7.5 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 3 N-(2- 2-chloro-pyridin-3- (600 MHz, CDCl₃) δ 11.53 (br s, chloropyridin- ylamine 1H), 9.00-8.88 (m, 1H), 8.16 (br 3-yl)-7- [CAS 6298-19-7] s, 1H), 7.82 (br. s., 1H), 7.59 (d, J = 8.6 Hz, methoxy-2-oxo- 1H), 7.38-7.24 (m, 1H), 8-propyl-2H- 7.06 (br. s., 3H), 6.99 (d, J = 8.5 Hz, chromene-3- 1H), 3.99 (s, 2 H), 2.87 (t, J = 7.6 Hz, carboxamide 1H), 1.74-1.50 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H). 4 7-methoxy-2- 2-trifluoromethyl- (600 MHz, CDCl₃) δ 11.25 (s, oxo-8-propyl-N- phenylamine 1H), 8.93 (s, 1H), 8.41 (d, J = 8.4 Hz, [2- [CAS 88-17-5] 1H), 7.68 (d, J = 7.8 Hz, 1H), (trifluoromethyl)phenyl]- 7.60 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H- 1H), 7.27 (t, J = 7.6 Hz, chromene-3- 1H), 6.97 (d, J = 8.7 Hz, 1H), carboxamide 3.98 (s, 3H), 2.86 (dd, J = 6.9, 8.5 Hz, 2H), 1.62 (sxt, J = 7.5 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 5 N-(2- 2-bromo- (600 MHz, CDCl₃) δ 11.32 (s, bromophenyl)- phenylamine 1H), 8.94 (s, 1H), 8.57 (dd, J = 1.5, 7-methoxy-2- [CAS 615-36-1] 8.4 Hz, 1H), 7.61 (dd, J = 1.4, oxo-8-propyl- 8.0 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H-chromene- 1H), 7.38-7.34 (m, 1H), 3-carboxamide 7.02 (td, J = 1.5, 7.7 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 2.86 (dd, J = 6.9, 8.5 Hz, 2H), 1.68-1.59 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 6 N-(3- 3-bromo-pyridin-4- (600 MHz, CDCl₃) δ 11.65 (br s, bromopyridin- ylamine 1H), 8.94 (s, 1H), 8.73 (br s, 1H), 4-yl)-7- [CAS 13534-98-0] 8.61 (br s, 1H), 8.49 (br s, 1H), methoxy-2-oxo- 7.61 (d, J = 8.7 Hz, 1H), 7.00 (d, 8-propyl-2H- J = 8.8 Hz, 1H), 4.00 (s, 3H), chromene-3- 2.87 (t, J = 7.6 Hz, 2H), carboxamide 1.69-1.56 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 7 7-methoxy-2- pyridin-4-ylamine (600 MHz, CDCl₃) δ 11.08 (s, oxo-8-propyl-N- [CAS 504-24-5] 1H), 8.92 (s, 1H), 8.56 (d, J = 5.1 Hz, pyridin-4-yl-2H- 2H), 7.67 (d, J = 6.3 Hz, 2H), chromene-3- 7.59 (d, J = 8.7 Hz, 1H), 6.99 (d, carboxamide J = 8.8 Hz, 1H), 3.98 (s, 3H), 2.91-2.83 (m, 2H), 1.63 (sxt, J = 7.5 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 8 7-methoxy-N- 3-methyl-pyridin-4- (600 MHz, CDCl₃) δ 11.17 (s, (3- ylamine 1H), 8.96 (s, 1H), 8.47-8.45 (m, methylpyridin- [CAS 1990-90-5] 1H), 8.43 (d, J = 5.4 Hz, 2H), 4-yl)-2-oxo-8- 8.43 (d, J = 5.4 Hz, 2H), 7.61 (d, propyl-2H- J = 8.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, chromene-3- 1H), 3.99 (s, 3H), 2.87 (dd, J = 6.9, carboxamide 8.5 Hz, 2H), 2.42 (s, 3H), 1.63 (sxt, J = 7.5 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 9 7-methoxy-2- 3-trifluoromethyl- (600 MHz, CDCl₃) δ 11.68 (s, oxo-8-propyl-N- pyridin-4-ylamine 1H), 8.93 (s, 1H), 8.85 (br s, 1H), [3- [CAS 387824-61-5] 8.74 (d, J = 5.0 Hz, 1H), 8.68 (d, (trifluoromethyl)pyridin- J = 5.6 Hz, 1H), 7.60 (d, J = 8.7 Hz, 4-yl]- 1H), 7.00 (d, J = 8.8 Hz, 1H), 2H-chromene- 4.00 (s, 3H), 2.88-2.84 (m, 2H), 3-carboxamide 1.66-1.58 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). 10 7-methoxy-2- pyridin-3-ylamine (600 MHz, CDCl₃) δ 10.99 (s, oxo-8-propyl-N- [CAS 462-08-8] 1H), 8.94 (s, 1H), 8.87 (br s, 1H), pyridin-3-yl-2H- 8.41 (br. s., 1H), 8.28 (ddd, J = 1.3, chromene-3- 2.3, 8.3 Hz, 1H), 7.59 (d, J = 8.7 Hz, carboxamide 1H), 7.34 (dd, J = 4.9, 8.1 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 2.91-2.85 (m, 2H), 1.68-1.59 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 11 7-methoxy-2- 2-trifluoromethyl- (600 MHz, CDCl₃) δ 11.45 (s, oxo-8-propyl-N- pyridin-3-ylamine 1H), 8.93 (s, 1H), 8.90 (d, J = 8.4 Hz, [2- [CAS 106877-32-1] 1H), 8.48 (dd, J = 1.2, 4.6 Hz, (trifluoromethyl)pyridin- 1H), 7.59 (d, J = 8.7 Hz, 1H), 3-yl]- 7.55 (dd, J = 4.6, 8.4 Hz, 1H), 2H-chromene- 6.99 (d, J = 8.7 Hz, 1H), 3.99 (s, 3-carboxamide 3H), 2.89-2.85 (m, 2H), 1.67-1.59 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 12 7-methoxy-N- 3-methyl-pyridin-2- (600 MHz, CDCl₃) δ 10.94 (br s, (3- ylamine 1H), 8.97 (s, 1H), 8.42 (d, J = 11.3 Hz, methylpyridin- [CAS 1603-40-3] 1H), 7.59 (d, J = 8.7 Hz, 2-yl)-2-oxo-8- 2H), 7.11 (br s, 1H), 6.98 (d, J = 8.8 Hz, propyl-2H- 1H), 3.98 (s, 3H), chromene-3- 2.89-2.85 (m, 2H), 2.39 (s, 3H), carboxamide 1.67-1.59 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 N-(3- 3-chloro-pyridazin-4- (600 MHz, CDCl₃) δ 11.85 (s, chloropyridazin- ylamine 1H), 9.02 (d, J = 5.6 Hz, 1H), 4-yl)-7- [CAS 55928-83-1] 8.92 (s, 1H), 8.71 (d, J = 5.6 Hz, methoxy-2-oxo- 1H), 7.62 (d, J = 8.7 Hz, 1H), 8-propyl-2H- 7.01 (d, J = 8.7 Hz, 1H), ), chromene-3- 4.00 (s, 3H), 2.91-2.83 (m, 2H), carboxamide 1.66-1.60 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). 14 N-(2-chloro-5- 2-chloro-5-fluoro- (600 MHz, CDCl₃) δ 11.63 (s, fluoropyridin-3- pyridin-3-ylamine 1H), 8.92 (s, 1H), 8.85 (dd, J = 2.8, yl)-7-methoxy- [CAS 884495-37-8] 10.1 Hz, 1H), 8.04 (d, J = 2.8 Hz, 2-oxo-8-propyl- 1H), 7.60 (d, J = 8.7 Hz, 1H), 2H-chromene- 7.00 (d, J = 8.7 Hz, 1H), 3.99 (s, 3-carboxamide 3H), 2.89-2.84 (m, 2H), 1.63 (dq, J = 7.5, 15.1 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 15 7-methoxy-N- 2-methyl-pyridin-3- (600 MHz, CDCl₃) δ 11.00 (s, (2- ylamine 1H), 8.94 (s, 1H), 8.69-8.62 (m, methylpyridin- [CAS 3430-10-2] 1H), 8.30 (dd, J = 1.5, 4.8 Hz, 3-yl)-2-oxo-8- 1H), 7.59 (d, J = 8.7 Hz, 1H), propyl-2H- 7.21 (dd, J = 4.8, 8.1 Hz, 1H), chromene-3- 6.99 (d, J = 8.7 Hz, 1H), 3.99 (s, carboxamide 3H), 2.87 (dd, J = 6.9, 8.4 Hz, 2H), 2.70 (s, 3H), 1.72-1.56 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 16 N-(2- 2-bromopyridin-3- (300 MHz, CDCl₃) δ 11.44 (s, 1H), bromopyridin- amine 8.91 (s, 1H), 8.87 (dd, J = 1.5, 8.4 Hz, 3-yl)-7- [CAS 39856-58-1] 1H), 8.13 (dd, J = 1.2, 4.2 Hz, methoxy-2-oxo- 1H), 7.58 (d, J = 9.0 Hz, 1H), 8-propyl-2H- 7.30 (dd, J = 4.8, 8.1 Hz, 1H), chromene-3- 6.98 (d, J = 8.7 Hz, 1H), 3.98 (s, carboxamide 3H), 2.85 (t, J = 7.8 Hz, 2H), 1.68-1.56 (m, 2H), 0.99 (t, J = 7.5 Hz, 3H). 18 N-(3- 3-chloropyridin-4- (300 MHz, DMSO-d₆) δ 11.54 (s, chloropyridin- amine 1H), 9.03 (s, 1H), 8.64 (s, 1H), 4-yl)-7- [CAS 19798-77-7] 8.51-8.46 (m, 2H), 7.96 (d, J = 8.7 Hz, methoxy-2-oxo- 1H), 7.23 (d, J = 9.0 Hz, 8-propyl-2H- 1H), 3.95 (s, 3H), 2.72 (t, J = 7.8 Hz, chromene-3- 2H), 1.58-1.50 (m, 2H), carboxamide 0.92 (t, J = 7.5 Hz, 3H). 19 N-(2- 2-ethylaniline [CAS (300 MHz, CDCl₃) δ10.88 (s, 1H), ethylphenyl)-7- 578-54-1] 8.95 (s, 1H), 8.29 (d, J = 8.1 Hz, methoxy-2-oxo- 1H), 7.57 (d, J = 9.0 Hz, 1H), 8-propyl-2H- 7.29-7.24 (m, 2H), 7.12 (t, J = 7.5 Hz, chromene-3- 1H), 6.97 (d, J = 8.4 Hz, 1H), carboxamide 3.97 (s, 3H), 2.89-2.76 (m, 4H), 1.69-1.56 (m, 2H), 1.32 (t, J = 7.8 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). 20 N-(2- 2-chloroaniline (300 MHz, CDCl₃) δ 11.42 (s, chlorophenyl)- [CAS 95-51-2] 1H), 8.93 (s, 1H), 8.60 (d, J = 7.8 Hz, 7-methoxy-2- 1H), 7.57 (d, J = 8.7 Hz, 1H), oxo-8-propyl- 7.43 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H-chromene- 1H), 7.08 (t, J = 8.1 Hz, 3-carboxamide 1H), 6.97 (d, J = 8.7 Hz, 1H), 3.97 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 1.66-1.54 (m, 2H), 0.99 (t, J = 7.8 Hz, 3H). 22 N-(2- 2-aminobenzonitrile (300 MHz, DMSO-d₆) δ 11.31 (s, cyanophenyl)- [CAS 1885-29-6] 1H), 9.00 (s, 1H), 8.41 (d, J = 8.1 Hz, 7-methoxy-2- 1H), 7.94 (d, J = 9.0 Hz, 1H), oxo-8-propyl- 7.85 (dd, J = 1.5, 8.1 Hz, 1H), 2H-chromene- 7.76-7.71 (m, 1H) 7.32 (t, J = 7.8 Hz, 3-carboxamide 1H), 7.22 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 2.74 (t, J = 8.1 Hz, 2H), 1.59-1.49 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H). 23 N-(2-chloro-5- 2-chloro-5- (300 MHz, CDCl₃) δ 11.45 (s, methylpyridin- methylaniline 1H), 8.90 (s, 1H), 8.77 (s, 1H), 3-yl)-7- [CAS 95-81-8] 7.98 (s, 1H), 7.58 (d, J = 8.7 Hz, methoxy-2-oxo- 1H), 6.98 (d, J = 9.0 Hz, 1H), 8-propyl-2H- 3.98 (s, 3H), 2.86 (t, J = 7.8 Hz, chromene-3- 2H), 2.37 (s, 3H), 1.66-1.57 (m, carboxamide 2H), 0.99 (t, J = 7.2 Hz, 3H). 24 7-methoxy-2- 2-propylaniline (600 MHz, CDCl₃) δ 10.85 (s, oxo-8-propyl-N- [CAS 1821-39-2] 1H), 8.95 (s, 1H), 8.28 (dd, J = 1.2, (2- 8.4 Hz, 1H), 7.57 (d, J = 9.0 Hz, propylphenyl)- 1H), 7.27-7.24 (m, 1H), 2H-chromene- 7.22 (dd, J = 1.2, 7.8 Hz, 1H), 3-carboxamide 7.12-7.09 (m, 1H), 6.96 (d, J = 9.0 Hz, 1H), 3.97 (s, 3H), 2.88-2.85 (m, 2H), 2.74 (t, J = 7.2 Hz, 2H), 1.74-1.68 (m, 2H), 1.66-1.60 (m, 2H), 1.04-0.98 (m, 6H). 26 7-methoxy-N- o-toluidine (300 MHz, DMSO-d₆) δ 10.68 (s, (2- [CAS 95-53-4] 1H), 8.98 (s, 1H), 8.19 (d, J = 8.2 Hz, methylphenyl)- 1H), 7.93 (d, J = 8.5 Hz, 1H), 2-oxo-8-propyl- 7.32-7.18 (m, 3H), 7.07 (d, J = 8.5 Hz, 2H-chromene- 1H), 3.95 (s, 3H), 2.75 (t, 3-carboxamide J = 6.9 Hz, 2H), 2.33 (s, 3H), 1.62-1.48 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 27 8-isopropoxy- Intermediate 4 (300 MHz, CDCl₃) δ11.37 (s, 1H), 7-methoxy-2- (used in place of 8.92 (s, 1H), 8.86 (d, J = 8.2 Hz, oxo-N-[2- Intermediate 1) and 1H), 8.47 (dd, J = 1.0, 4.5 Hz, (trifluoromethyl)pyridin- 2-Trifluoromethyl- 1H), 7.55 (dd, J = 4.5, 8.5 Hz, 3-yl]- pyridin-3-ylamine 1H), 7.45 (d, J = 8.6 Hz, 1H), 2H-chromene- [CAS 106877-32-1] 7.01 (d, J = 8.8 Hz, 1H), 3-carboxamide 4.71-4.54 (m, 1H), 4.00 (s, 3H), 1.39 (d, J = 6.2 Hz, 6H). 28 8-isopropoxy- Intermediate 4 (300 MHz, CDCl₃) δ 10.93 (s, 7-methoxy-N- (used in place of 1H), 8.94 (s, 1 H), 8.63 (dd, J = 1.5, (2- Intermediate 1) and 8.2 Hz, 1H), 8.30 (dd, J = 1.5, methylpyridin- 2-Methyl-pyridin-3- 4.7 Hz, 1H), 7.46 (d, J = 8.8 Hz, 3-yl)-2-oxo-2H- ylamine 1H), 7.21 (dd, J = 4.8, 8.2 Hz, chromene-3- [CAS 340-10-2] 1H), 7.02 (d, J = 8.8 Hz, 1H), carboxamide 4.61 (dt, J = 6.2, 12.4 Hz, 1H), 4.00 (s, 3H), 2.69 (s, 3H), 1.41 (d, 6H). 29 8-ethoxy-7- Intermediate 5 (600 MHz, CDCl₃) δ 10.93 (br s, methoxy-N-(2- (used in place of 1H), 8.96-8.93 (m, 1H), 8.63 (d, J = 8.0 Hz, methylpyridin- Intermediate 1) and 1H), 8.31 (d, J = 3.5 Hz, 3-yl)-2-oxo-2H- 2-Methyl-pyridin-3- 1H), 7.47 (d, J = 8.7 Hz, 1H), chromene-3- ylamine 7.21 (dd, J = 4.8, 8.0 Hz, 1H), carboxamide [CAS 3430-10-2] 7.03 (d, J = 8.7 Hz, 1H), 4.30-4.22 (m, 2H), 4.02 (s, 3H), 2.69 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H). 30 8-ethoxy-7- Intermediate 5 (300 MHz, CDCl₃) δ 11.37 (s, methoxy-2-oxo- (used in place of 1H), 8.93 (s, 1H), 8.87 (d, J = 8.4 Hz, N-[2- Intermediate 1) 1H), 8.58-8.41 (m, 1H), (trifluoromethyl)pyridin- 2-Trifluoromethyl- 7.56 (dd, J = 4.6, 8.4 Hz, 1H), 7.46 (d, 3-yl]- pyridin-3-ylamine J = 8.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H-chromene- [106877-32-1] 1H), 4.26 (q, J = 7.1 Hz, 2H), 3-carboxamide 4.02 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H). 31 8-ethoxy-7- Intermediate 5 (600 MHz, CDCl₃) δ 11.17 (br s, methoxy-2-oxo- (used in place of 1H), 8.93 (s, 1H), 8.37 (d, J = 8.2 Hz, N-[2- Intermediate 1) and 1H), 7.68 (d, J = 7.6 Hz, 1H), (trifluoromethyl)phenyl]- 2-Trifluoromethyl- 7.60 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H- phenylamine 1H), 7.28 (t, J = 7.5 Hz, chromene-3- [CAS 95-53-4] 1H), 7.01 (d, J = 8.8 Hz, 1H), carboxamide 4.26 (q, J = 7.0 Hz, 2H), 4.01 (s, 3H), 1.47 (t, 3H). 32 8-isopropoxy- Intermediate 4 (600 MHz, CDCl₃) δ 11.18 (br s, 7-methoxy-2- (used in place of 1H), 8.93 (s, 1H), 8.38 (d, J = 8.2 Hz, oxo-N-[2- Intermediate 1) and 1H), 7.68 (d, J = 7.8 Hz, 1H), (trifluoromethyl)phenyl]- 2-trifluoromethoxy- 7.60 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H- phenylamine 1H), 7.28 (t, J = 7.5 Hz, chromene-3- [CAS 88-17-5] 1H), 7.01 (d, 1H) 4.63 (dt, J = 12.3, carboxamide 6.2 Hz, 1H), 4.00 (s, 3 H), 1.42-1.36 (m, 7H). 33 7-methoxy-N- 2-methoxy- (600 MHz, CDCl₃) δ 11.35 (s, (2- phenylamine 1H), 8.91 (s, 1H), 8.58 (dd, J = 1.4, methoxyphenyl)- [CAS 90-04-0] 8.0 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2-oxo-8- 1H), 7.13-7.07 (m, 1H), propyl-2H- 7.04-6.98 (m, 1H), 6.98-6.92 (m, 2H), chromene-3- 3.97 (d, J = 10.3 Hz, 6H), carboxamide 2.89-2.81 (m, 2H), 1.62 (sxt, J = 7.5 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). 34 7-methoxy-N- 2-methylsulfanyl- (600 MHz, CDCl₃) δ 11.48 (s, [2- phenylamine [CAS 1H), 8.94 (s, 1H), 8.52 (dd, J = 1.2, (methylthio)phenyl]- 2987-53-3] 8.2 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2-oxo-8- 1H), 7.53 (dd, J = 1.5, 7.8 Hz, propyl-2H- 1H), 7.36-7.31 (m, 1H), 7.12 (td, chromene-3- J = 1.3, 7.6 Hz, 1H), 6.97 (d, J = 8.7 Hz, carboxamide 1H), 3.97 (s, 3H), 2.86 (dd, J = 6.9, 8.5 Hz, 2H), 2.47 (s, 3H), 1.66-1.60 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). 35 N-[2-(2- 2-furan-2-yl- (600 MHz, CDCl₃) δ 11.21 (s, furyl)phenyl]-7- phenylamine 1H), 8.93 (s, 1H), 8.36 (d, J = 7.6 Hz, methoxy-2-oxo- [CAS 55578-79-5] 1H), 7.65-7.62 (m, 2H), 8-propyl-2H- 7.55 (d, J = 8.7 Hz, 1H), 7.40-7.35 (m, chromene-3- 1H), 7.22 (td, J = 1.2, 7.6 Hz, carboxamide 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 3.4 Hz, 1H), 6.57 (dd, J = 1.8, 3.3 Hz, 1H), 3.97 (s, 3H), 2.86 (dd, J = 6.9, 8.5 Hz, 2H), 1.62 (sxt, J = 7.5 Hz, 2H), 0.99 (t, J = 7.3, 3 H). 36 N-[4- (4-aminophenyl)methanol (300 MHz, DMSO-d₆) δ 10.90 (s, (hydroxymethyl)phenyl]- [CAS 623-04-1] 1H), 8.93 (s, 1H), 7.74 (d, J = 8.5 Hz, 7- 2H), 7.57 (d, J = 8.8 Hz, 1H), methoxy-2-oxo- 7.38 (d, J = 8.5 Hz, 2H), 6.97 (d, 8-propyl-2H- J = 7.9 Hz, 1H), 4.69 (s, 2H), chromene-3- 3.97 (s, 3H), 2.86 (t, J = 7.8 Hz, carboxamide 2H), 1.70-1.57 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 37 7-methoxy-N- N-(4-amino-3- (300 MHz, CDCl₃δ 11.28 (s, 1H), {4- (trifluoromethyl)phenyl)methanesulfonamide 8.94 (s, 1H), 8.37 (d, J = 8.7 Hz, [(methylsulfonyl)amino]- [CAS 1H), 7.60-7.54 (m, 2H), 2- 926228-44-6] 7.48-7.45 (m, 1H), 6.98 (d, J = 9.0 Hz, 1H), (trifluoromethyl)phenyl}- 6.68 (s, 1H), 3.98 (s, 3H), 3.05 (s, 2-oxo- 3H), 2.85 (t, J = 7.5 Hz, 2H), 8-propyl-2H- 1.65-1.58 (m, 2H), 0.99 (t, J = 7.5 Hz, chromene-3- 3H). carboxamide 38 N-[4- 4-amino-3- (300 MHz, DMSO-d₆) δ 11.41 (s, (aminosulfonyl)- bromobenzenesulfonamide 1H), 9.03 (s, 1H), 8.70-8.66 (m, 2- [CAS 1H), 8.10-8.08 (m, 1H), 7.96 (d, J = 8.4 Hz, bromophenyl]- 53297-69-1] 1H), 7.88-7.84 (m, 1H), 7-methoxy-2- 7.44 (s, 2H), 7.24 (d, J = 7.8 Hz, oxo-8-propyl- 1H), 3.96 (s, 3H), 2.80-2.65 (m, 2H-chromene- 2H), 1.60-1.50 (m, 2H), 0.92 (t, J = 6.9 Hz, 3-carboxamide 3H). 39 N-[4- 4-amino-3- (300 MHz, DMSO-d₆) δ 11.51 (s, (aminosulfonyl)- chlorobenzenesulfonamide 1H), 9.02 (s, 1H), 8.71 (d, J = 4.2 Hz, 2- [CAS 53297-68-0] 1H), 7.96-7.94 (m, 2H), chlorophenyl]- 7.81 (dd, J = 0.6, 4.2 Hz, 1H), 7.43 (s, 7-methoxy-2- 2H), 7.23 (d, J = 4.8 Hz, 1H), oxo-8-propyl- 3.95 (s, 3H), 2.73 (t, J = 3.9 Hz, 2H-chromene- 2H), 1.56-1.52 (m, 2H), 0.91 (t, J = 3.6 Hz, 3-carboxamide 3H). 40 N-[4- 4-aminobenzene (300 MHz, DMSO-d₆) δ 10.89 (s, (aminosulfonyl)phenyl]- sulfonamide 1H), 8.88 (s, 1H), 7.95-7.78 (m, 7- [CAS 63-74-1] 5H), 7.32 (s, 2H), 7.23 (d, J = 8.8 Hz, methoxy-2-oxo- 1H), 3.96 (s, 3H), 8-propyl-2H- 2.80-2.70 (m, 2H), 1.61-1.51 (m, 2H), chromene-3- 0.93 (t, J = 7.4 Hz, 3H). carboxamide 43 7-methoxy-N- 2-methoxypyridin-3- (600 MHz, CDCl₃) δ 11.28 (s, (2- amine 1H), 8.87 (s, 1H), 8.76 (dd, J = 1.8, methoxypyridin- [CAS 20265-38-7] 7.8 Hz, 1H), 7.89 (dd, J = 1.8, 3-yl)-2-oxo-8- 5.4 Hz, 1H), 7.54 (d, J = 9.0 Hz, propyl-2H- 1H), 6.95-6.91 (m, 2H), chromene-3- 4.10 (s, 3H), 3.96 (s, 3H), carboxamide 2.86-2.84 (m, 2H), 1.64-1.58 (m, 2H), 0.98 (t, J = 7.8 Hz, 3H). 44 7-methoxy-N- N-(5-amino-6- (300 MHz, DMSO-d₆) δ 11.10 (s, {2-methoxy-4- methoxypyridin-2-yl)methanesulfonamide 1H), 9.64 (br s, 1H), 8.95 (s, 1H), [(methylsulfonyl)amino]phenyl}- [CAS 57165-06-7] 8.37 (d, J = 8.7 Hz, 1H), 7.91 (d, 2-oxo-8- J = 8.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, propyl-2H- 1H) 6.93 (d, J = 2.4 Hz, 1H), chromene-3- 6.81 (dd, J = 2.4, 8.7 Hz, 1H), carboxamide 3.94 (s, 3H), 3.87 (s, 3H), 2.96 (s, 3H), 2.73 (t, J = 6.9 Hz, 2H), 1.58-1.50 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H). 45 N-(4-hydroxy-2- 4-amino-3- (300 MHz, DMSO-d₆) δ 10.38 (s, methylphenyl)- methylphenol 1H), 9.25 (s, 1H), 8.92 (s, 1H), 7-methoxy-2- [CAS 2835-99-6] 7.90 (d, J = 8.7 Hz, 1H), 7.82 (d, oxo-8-propyl- J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H-chromene- 1H), 6.65-6.59 (m, 2H), 3-carboxamide 3.94 (s, 3H), 2.74 (t, J = 8.1 Hz, 2H), 2.22 (s, 3H), 1.58-1.50 (m, 2H), 0.92 (t, J = 7.8 Hz, 3H). 47 N-[4- N-(4-amino-3- (300 MHz, CDCl₃) δ 11.18 (s, (acetylamino)- (trifluoromethyl)phenyl)acetamide 1H), 8.91 (s, 1H), 8.31 (d, J = 9.3 Hz, 2- [CAS 1H), 7.88 (s, 1H), 7.69 (d, J = 8.7 Hz, (trifluoromethyl)phenyl]- 1579-89-1] 1H), 7.56 (d, J = 8.7 Hz, 7- 1H), 7.32 (s, 1H), 6.97 (d, J = 8.4 Hz, methoxy-2-oxo- 1H), 3.97 (s, 3H), 8-propyl-2H- 2.88-2.81 (m, 2H), 2.20 (s, 3H), chromene-3- 1.65-1.58 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H). carboxamide 48 N-[2- 2-(difluoromethoxy)aniline (300 MHz, CDCl₃) δ 11.37 (s, (difluoromethoxy)phenyl]- [CAS 22236-04-0] 1H), 8.90 (s, 1H), 8.61 (d, J = 8.1 Hz, 7- 1H), 7.56 (d, J = 8.7 Hz, 1H), methoxy-2-oxo- 7.29-7.21 (m, 2H), 7.14-7.09 (m, 8-propyl-2H- 1H), 6.96 (d, J = 8.7 Hz, 1H), chromene-3- 6.66 (t, J = 73.2 Hz, 1H), 3.96 (s, carboxamide 3H), 2.85 (t, J = 7.5 Hz, 2H), 1.65-1.57 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H). 51 N-[4- N-(4-amino-3- (300 MHz, CDCl₃) δ 10.81 (s, (acetylamino)- methylphenyl)acetamide 1H), 8.93 (s, 1H), 8.23 (d, J = 8.7 Hz, 2- [CAS 6375-20-8] 1H), 7.57 (d, J = 8.7 Hz, 1H), methylphenyl]- 7.51 (s, 1H), 7.26-7.24 (m, 1H), 7-methoxy-2- 7.13 (s, 1H), 6.97 (d, J = 8.7 Hz, oxo-8-propyl- 1H), 3.97 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H-chromene- 2H), 2.41 (s, 3H), 2.17 (s, 3-carboxamide 3H), 1.66-1.56 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 54 N-(2- 3- (300 MHz, CDCl₃) δ 12.85 (s, formylpyridin- aminopicolinaldehyde 1H), 10.19 (s, 1H), 9.27 (d, J = 8.7 Hz, 3-yl)-7- [CAS 55234-58-7] 1H), 8.87 (s, 1H), 8.54 (d, methoxy-2-oxo- J = 4.5 Hz, 1H), 7.57-7.52 (m, 8-propyl-2H- 2H), 6.96 (d, J = 8.7 Hz, 1H), chromene-3- 3.97 (s, 3H), 2.86 (t, J = 7.5 Hz, carboxamide 2H), 1.66-1.58 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 56 N-{2-chloro-4- N-(4-amino-3- (600 MHz, DMSO-d₆) δ 11.18 (s, [(methylsulfonyl)amino]phenyl}- chlorophenyl)methanesulfonamide 1H), 9.91 (s, 1H), 9.01 (s, 1H), 7-methoxy-2- [CAS 57165-03-4] 8.45 (d, J = 9.0 Hz, 1H), 7.95 (d, oxo-8-propyl- J = 9.0 Hz, 1H), 7.37 (s, 1H), 2H-chromene- 7.25-7.23 (m, 2H), 3.97 (s, 3H), 3-carboxamide 3.03 (s, 3H), 2.75 (t, J = 6.6 Hz, 2H), 1.58-1.54 (m, 2H), 0.93 (t, J = 7.8 Hz, 3H). 57 7-methoxy-2- tert-butyl 2-(((4- (600 MHz, CDCl₃) δ 10.64 (s, oxo-N-{4- aminophenyl)amino)methyl)piperidine- 1H), 8.90 (s, 1H), 7.57-7.49 (m, [(piperidin-2- 1- 3H), 6.96 (d, J = 8.8 Hz, 1H), ylmethyl)amino]phenyl}- carboxylate 6.64 (d, J = 8.8 Hz, 2H), 4.03 (br. 8- [CAS 1159976-36- s., 1H), 3.97 (s, 3H), 3.17 (d, J = 12.6 Hz, propyl-2H- 9] followed by 1H), 3.13-3.08 (m, 1H), chromene-3- deprotection with 3.06-2.94 (m, 2H), 2.90-2.84 (m, carboxamide HCl in CH₂Cl₂. 2H), 2.82-2.75 (m, 2H), 2.64 (td, J = 2.6, 11.8 Hz, 2H), 1.88-1.82 (m, 1H), 1.65-1.58 (m, 2H), 1.47-1.36 (m, 2H), 1.27-1.15 (m, 1H), 0.99 (t, J = 7.3 Hz, 3H). 58 7-methoxy-2- tert-butyl 3-(((4- (600 MHz, CDCl₃) δ 10.64 (s, oxo-N-{4- aminophenyl)amino)methyl)piperidine- 1H), 8.90 (s, 1H), 7.58-7.51 (m, [(piperidin-3- 1- 3H), 6.96 (d, J = 8.7 Hz, 1H), ylmethyl)amino]phenyl}- carboxylate 6.61 (d, J = 8.8 Hz, 2H), 3.97 (s, 8- [CAS 1159976-35- 3H), 3.22-3.14 (m, 1H), 3.03 (d, J = 12.3 Hz, propyl-2H- 8] followed by 2H), 3.01-2.96 (m, chromene-3- deprotection with 2H), 2.89-2.84 (m, 2H), carboxamide HCl in CH₂Cl₂ 2.63-2.57 (m, 1H), 2.40 (dd, J = 10.4, 11.7 Hz, 1H), 1.92 (dt, J = 1.8, 13.0 Hz, 1H), 1.80 (ddd, J = 3.6, 7.0, 13.9 Hz, 1H), 1.77-1.71 (m, 1H), 1.71-1.68 (m, 1H), 1.66-1.59 (m, 2H), 1.55-1.44 (m, 1H), 1.18 (qd, J = 3.8, 12.0 Hz, 1H), 0.99 (t, J = 7.3 Hz, 3H). 59 7-methoxy-2- tert-butyl 3-((4- (300 MHz, CDCl₃) δ 10.66 (s, oxo-8-propyl-N- aminophenyl)amino)pyrrolidine- 1H), 8.91 (s, 1H), 7.56 (d, J = 4.4 Hz, [4-(pyrrolidin-3- 1- 1H), 7.54 (d, J = 4.7 Hz, 2H), ylamino)phenyl]- carboxylate 6.96 (d, J = 8.8 Hz, 1H), 6.63 (d, 2H-chromene- [CAS 1159976-32- J = 8.8 Hz, 2H), 4.00-3.97 (m, 3-carboxamide 5] followed by 1H), 3.97 (s, 3H), 3.61 (q, J = 7.2 Hz, deprotection with 1H), 3.18 (dd, J = 5.9, 11.4 Hz, HCl in CH₂Cl₂. 1H), 3.13 (ddd, J = 7.1, 7.5, 10.6 Hz, 1H), 2.98 (ddd, J = 6.0, 8.3, 10.9 Hz, 1H), 2.90 (dd, J = 2.9, 11.4 Hz, 1H), 2.88-2.85 (m, 2H), 2.23-2.16 (m, 1H), 1.65-1.58 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 60 7-methoxy-2- tert-butyl 3-((4- (600 MHz, CDCl₃) δ 10.64 (s, oxo-N-[4- aminophenyl)amino)piperidine- 1H), 8.90 (s, 1H), 7.54 (dd, J = 8.8, (piperidin-3- 1- 14.4 Hz, 3H), 6.96 (d, J = 8.7 Hz, ylamino)phenyl]- carboxylate 1H), 6.64 (d, J = 9.0 Hz, 2H), 8-propyl-2H- [CAS 1159976-34- 3.97 (s, 3H), 3.45 (d, J = 3.2 Hz, chromene-3- 7] followed by 1H), 3.23 (dd, J = 2.4, 11.6 Hz, carboxamide deprotection with 1H), 2.94-2.88 (m, 1H), HCl in CH₂Cl₂. 2.88-2.84 (m, 2H), 2.76-2.70 (m, 1H), 2.58 (dd, J = 7.6, 11.3 Hz, 1H), 1.98-1.92 (m, 1H), 1.80-1.70 (m, 5H), 1.62 (dq, J = 7.5, 15.0 Hz, 2H), 1.58-1.48 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H). 61 (3S)-3-amino-4- (S)-4-(tert-butoxy)-2- (300 MHz, CDCl₃) δ 10.82 (s, [(4-{[(7- ((tert- 1H), 9.48 (s, 1H), 8.95 (s, 1H), methoxy-2-oxo- butoxycarbonyl)amino)- 8.26 (d, J = 8.9 Hz, 1H), 8-propyl-2H- 4-oxobutanoic 7.64-7.60 (m, 1H), 7.58 (d, J = 8.8 Hz, chromen-3- acid 1H), 7.42-7.34 (m, 1H), 6.98 (d, J = 8.6 Hz, yl)carbonyl]amino}- [CAS 3057-74-7] 1H), 3.98 (s, 3H), 3- followed by the 3.84-3.73 (m, 1H), 3.69-3.62 (m, 1H), methylphenyl)amino]- deprotection with 2.93-2.80 (m, 2H), 2.73-2.60 (m, 4- HCl in CH₂Cl₂. 1H), 2.43 (s, 3H), 1.69-1.59 (m, oxobutanoic 2H), 1.00 (t, J = 7.3 Hz, 3H). acid 62 (4R)-4-amino-5- (R)-5-(tert-butoxy)-2- (600 MHz, DMSO-d₆, 1-drop of [(4-{[(7- ((tert- AcOD-d₄) δ 8.93 (s, 1H), 8.18 (d, methoxy-2-oxo- butoxycarbonyl)amino)- J = 8.7 Hz, 1H), 7.85 (d, J = 8.7), 8-propyl-2H- 5-oxopentanoic 7.48 (s, 1H), 7.46 (d, J = 8.8 Hz, chromen-3- acid 1H), 7.16 (d, J = 8.7 Hz, 1H), yl)carbonyl]amino}- [CAS 104719-63-3] 3.96 (t, J = 6.5 Hz, 1H), 3.93 (s, 3- followed by the 3H), 2.74 (t, J = 7.5 Hz, 2H), methylphenyl)amino]- deprotection with 2.41-2.37 (m, 2H), 2.32 (s, 3 H), 5- HCl in CH₂Cl₂. 2.08 (q, J = 7.3 Hz, 2H), oxopentanoic 1.58-1.49 (m, 2H), 0.91 (t, 3H). acid 63 N-[4- Intermediate 3 (300 MHz, DMSO-d₆) δ 10.89 (s, (aminosulfonyl)- (used in place of 1H), 8.99 (s, 1H), 8.42 (d, J = 8.2 Hz, 2- Intermediate 1) and 1H), 7.79 (d, J = 9.1 Hz, 1H), methylphenyl]- 4-amino-3- 7.73-7.71 (m, 1H), 7.71-7.66 (m, 7,8-diethoxy-2- methylbenzenesulfonamide 1H), 7.23-7.28 (m, 3H), 4.24 (q, J = 6.9 Hz, oxo-2H- [CAS 2H), 4.12 (q, J = 7.0 Hz, chromene-3- 53297-70-4] 2H), 2.41 (s, 3H), 1.39 (t, J = 7.0 Hz, carboxamide 3H), 1.32 (t, J = 7.0 Hz, 3H). 64 N-[4- Intermediate 5 (300 MHz, DMSO-d₆) δ 10.88 (s, (aminosulfonyl)- (used in place of 1H), 9.00 (s, 1H), 8.42 (d, J = 8.2 Hz, 2- Intermediate 1) and 1H), 7.81 (d, J = 9.1 Hz, 1H), methylphenyl]- 4-amino-3- 7.74-7.69 (m, 1H), 7.67 (d, J = 1.8 Hz, 8-ethoxy-7- methylbenzenesulfonamide 1H), 7.28 (s, 1H), 7.26 (s, methoxy-2-oxo- [CAS 53297-70-4 2H), 4.11 (q, J = 7.0 Hz, 2H), 2H-chromene- 3.96 (s, 3H), 2.41 (s, 3H), 1.32 (t, 3-carboxamide J = 7.0 Hz, 3H). 65 N-[4- 8-isopropoxy-7- (300 MHz, DMSO-d₆) δ 10.90 (s, (aminosulfonyl)- methoxy-2-oxo-2H- 1H), 9.00 (s, 1H), 8.43 (d, J = 8.5 Hz, 2- chromene-3- 1H), 7.81 (d, J = 9.1 Hz, 1H), methylphenyl]- carboxylic acid and 7.73-7.69 (m, 1H), 7.68-7.66 (m, 8-isopropoxy- 4-amino-3- 1H), 7.28 (m, 1H), 7.25 (s, 2H), 7-methoxy-2- methylbenzenesulfonamide 4.50-4.40 (m, 1H), 3.95 (s, 3H), oxo-2H- [CAS 53297-70-4] 2.41 (s, 3H), 1.28 (d, J = 6.2 Hz, chromene-3- 6H). carboxamide 69 7,8-diethoxy-N- Intermediate 3 (300 MHz, CDCl₃) δ11.20 (s, 1H), {4- (used in place of 8.94 (s, 1H), 8.29 (d, J = 9.0 Hz, [(methylsulfonyl)amino]- Intermediate 1) and 1H), 7.56 (d, J = 2.4 Hz, 1H), 2- N-(4-amino-3- 7.46-7.42 (m, 2H), 6.99 (d, J = 9.0 Hz, (trifluoromethyl)phenyl}- (trifluoromethyl)phenyl)methanesulfonamide 1H), 6.94 (s, 1H), 2-oxo- [CAS 926228-44-6] 4.28-4.20 (m, 4H), 3.05 (s, 3H), 2H-chromene- 1.55-1.43 (m, 6H). 3-carboxamide 70 7-methoxy-2- 2-trifluoromethoxy- (600 MHz, CDCl₃) δ 11.41 (s, oxo-8-propyl-N- phenylamine 1H), 8.92 (s, 1H), 8.65 (dd, J = 1.3, [2- [CAS 1535-75-7] 8.2 Hz, 1H), 7.57 (d, J = 8.7 Hz, (trifluoromethoxy)phenyl]- 1H), 7.38-7.30 (m, 2H), 2H- 7.18-7.11 (m, 1H), 6.97 (d, J = 8.7 Hz, chromene-3- 1H), 3.98 (s, 3H), 2.89-2.84 (m, carboxamide 2H), 1.62 (sxt, J = 7.5 Hz, 2H), 1.00-0.97 (m, 2H). 71 N-[4- Intermediate 2 (300 MHz, DMSO-d₆) δ 10.93 (s, (aminosulfonyl)- (used in place of 1H), 9.01 (s, 1H), 8.44 (d, J = 8.2 Hz, 2- Intermediate 1) and 1H), 7.95 (d, J = 8.8 Hz, 1H), methylphenyl]- 4-amino-3- 7.74-7.65 (m, 2H), 7.28-7.20 (m, 8-ethyl-7- methylbenzenesulfonamide 3H), 3.97 (s, 3H), 2.84-2.74 (m, methoxy-2-oxo- [CAS 53297-70-4] 2H), 2.41 (s, 3H), 1.12 (t, J = 7.5 Hz, 2H-chromene- 3H). 3-carboxamide 72 N-[4- 4-amino-3- (300 MHz, DMSO-d₆) δ 11.48 (s, (aminosulfonyl)- trifluoromethylbenzenesulfonamide 1H), 8.73 (s, 1H), 7.94 (d, J = 2.4 Hz, 2- [CAS 39234-84-9] 1H), 7.84-7.79 (m, 2H), (trifluoromethyl)phenyl]- 7.18 (d, J = 9.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 7- 1H), 6.73 (s, 1H), 3.92 (s, methoxy-2-oxo- 1H), 2.69 (t, J = 7.8 Hz, 2H), 8-propyl-2H- 1.54-1.47 (m, 2H), 0.88 (t, J = 7.8 Hz, chromene-3- 3H). carboxamide

EXAMPLE 6 Compound 17 N-(2-Ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide

Step 1: A mixture of 2-bromo-3-nitropyridine [CAS 19755-53-4] (0.600 g, 2.90 mmol), LiCl (0.80 g, 0.019 mmol), PdCl₂(PPh₃)₂ (0.20 g, 0.280 mmol) and tributyl(vinyl)stannane (1.0 g, 3.42 mmol) in DMF (5 mL) was heated at 90° C. overnight. After standard aqueous work up, the crude was purified by MPLC using (10% EtOAC/Hexanes) and gave a yellow oil.

Step 2: The yellow oil (0.25 g, 2.08 mmol) was hydrogenated at 50 psi over 10% Pd/C in MeOH (10 mL) for 16 hours. The mixture was then filtered and purified by MPLC using (5% MeOH in CH₂Cl₂) to give 2-ethylpyridin-3-amine as a solid.

Step 3: 2-Ethylpyridin-3-amine was substituted in the method used in Example 1.

¹H NMR (300 MHz, CDCl₃) δ 11.03 (s, 1H), 8.94 (s, 1H), 8.64 (d, J=8.1 Hz, 1H), 8.34 (d, J=4.8 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.20 (dd, J=4.8, 8.4 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 3.98 (s, 3H), 3.00 (q, J=7.5 Hz, 2H), 2.87 (t, J=7.8 Hz, 2H), 1.67-1.59 (m, 2H), 1.40 (t, J=7.5 Hz, 3H), 1.00 (t, J=7.5 Hz, 3H).

EXAMPLE 7 Compound 21 (4-{[(7-Methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)phosphonic acid

Step 1: A solution of 4-iodo-2-methylaniline [CAS 13194-68-8] (0.51 g, 2.21 mmol), diethyl phosphonate (0.30 mL, 2.32 mmol), TEA (0.325 mL, 2.33 mmol), Pd(PPh₃)₄ (cat.) was heated at 90° C. overnight. The solution was cooled to room temperature and EtOAc was added. After standard aqueous work up, the crude was purified by MPLC (30-50% EtOAc/Hexanes) and used in the next step.

Step 2: Diethyl (4-amino-3-methylphenyl)phosphonate was substituted in the method used in Example 1.

Step 3: A solution of the previous amide from Step 2 (0.08, 0.164 mmol), bromotrimethylsilane (0.55 g, 3.41 mmol) in CH₃CN (5 mL) was heated at 80° C. overnight. After solution was allowed to cool to room temperature, evaporation to remove volatiles was done. The residue was purified by MPLC (NH₃/MeOH) followed by trituration in CHCl₃ then MeOH to give Compound 21 as a yellow solid.

¹H NMR (600 MHz, d-TFA) δ 9.32 (s, 1H), 8.24 (br s, 1H), 7.95-7.89 (m, 2H), 7.87 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 4.14 (s, 3H), 3.02 (t, J=6.6 Hz, 2H), 2.59 (s, 3H), 1.78-1.70 (m, 2H), 1.08 (t, J=7.2 Hz, 3H).

EXAMPLE 8 Compound 25 (3-Chloro-4-{[(7-methoxy-2-oxo-8-propyl-2H -chromen -3-yl)carbonyl]amino}phenyl)boronic acid

Step 1: 2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [CAS 721960-43-6] is substituted in the method used in Example 1.

Step 2: To a mixture of the amide from Step 1 (0.15 g, 0.302 mmol) in THF/MeOH/H₂O was added NaIO₄ (0.22 g, 1.03 mmol) at room temperature with stirring for 30 minutes. 1N HCl (0.30 mL, 0.30 mmol) was then added and stirring was allowed for 2 days. After 2 days water was added and the solid was filtered. The solid was washed with EtOAc and purified by MPLC (5% MeOH/CH₂Cl₂) to give the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.99 (s, 1H), 8.54-8.46 (m, 1H), 8.17 (s, 2H), 7.96-7.86 (m, 2H), 7.76-7.74 (m, 1H), 7.24-7.16 (m, 1H), 3.94 (s, 3H), 2.80-2.65 (m, 2H), 1.65-1.45 (m, 2H), 1.0-0.84 (m, 3H).

EXAMPLE 9 Compound 41 N-(4-Amino-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide

Step 1: tert-Butyl (4-amino-3-methylphenyl)carbamate [CAS 325953-41-1] was substituted in the method used in Example 1.

Step 2: The compound from Step 1 (0.48 g, 1.03 mmol) in CH₂Cl₂ (25 mL) was treated with 4.0 M HCl in Dioxane (3.40 mL, 13.6 mmol) at room temperature and stirred overnight. The solution was evaporated and then triturated with ether followed by filtration to give the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 0.70 (s, 1H), 8.96 (s, 1H), 8.23 (d, J=9.6 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.24-7.16 (m, 3H), 3.95 (s, 3H), 3.55 (br s, 3H), 2.73 (t, J=8.1 Hz, 2H), 2.34 (s, 3H), 1.56-1.53 (m, 2H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 10 Compound 42 N-(6-Amino-2-methylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide

Step 1: 6-Methyl-5-nitropyridin-2-amine [CAS 22280-62-2] (0.38 g, 2.48 mmol) was hydrogenated at 50 psi with 10% Pd/C (0.35 g) in MeOH/THF (10 mL) overnight to give 6-methylpyridine-2,5-diamine as a light yellow solid.

Step 2: 6-methylpyridine-2,5-diamine was substituted in the method used in Example 1. ¹H NMR (300 MHz, CDCl₃) δ 10.61 (s, 1H), 8.90 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.43 (d, J=9.0 Hz, 1H), 4.39 (br s, 2H), 3.97 (s, 3H), 2.88-2.84 (m, 2H), 2.48 (s, 3H), 1.70-1.60 (m, 2H), 0.99 (t, J=7.2 Hz, 3H).

EXAMPLE 11 Compound 46 7-Methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide

Compound 42 (0.20 g, 0.545 mmol) was treated with TEA (0.15 mL, 1.08 mmol) and methanesulfonyl chloride (0.90 mL) in DMF (20 mL) at 0° C. The reaction was stirred overnight at room temperature then heated to 40° C. overnight. After standard aqueous workup, the crude was purified by MPLC (50% EtOAc/Hexanes) to give the title compound.

¹H NMR (600 MHz, DMSO-d₆) δ 10.55 (s, 1H), 10.39 (s, 1H), 8.93 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 3.94 (s, 3H), 3.29 (s, 3H), 2.73 (t, 7.8, 2H), 2.44 (s, 3H), 1.56-1.52 (m, 2H), 0.90 (t, J=7.8 Hz, 3H).

Compounds 49, 52 and 53 were prepared in a similar manner to the method described in Example 11 for Compound 46. The reagents used and the results are described below in Table 2.

TABLE 2 Compound ¹H NMR δ (ppm) for number IUAPC name Reagent (s) used Compound 49 N-{4- Compound 41 was (300 MHz; CDCl₃) δ 10.86 (s, [(ethylsulfonyl)amino]- used in place of 1H), 8.95 (s, 1H), 8.23 (d, J = 8.4 Hz, 2- Compound 42 1H), 7.59 (d, J = 8.7 Hz, methylphenyl}- Ethanesulfonyl 1H), 7.15 (d, J = 2.4 Hz, 1H), 7-methoxy-2- chloride was used in 7.08 (dd, J = 2.4, 8.4 Hz, 1H), oxo-8-propyl- place of 6.98 (d, J = 9.0 Hz, 1H), 2H-chromene- methanesulfonyl 6.54 (s, 1H), 3.98 (s, 3H), 3.12 (q, J = 7.5 Hz, 3-carboxamide chloride 2H), 2.88-2.84 (m, 2H), 2.41 (s, 3H), 1.70-1.57 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). 52 7-methoxy-N- Compound 41 was (300 MHz, DMSO-d₆) δ 10.58 {2-methyl-4- used in place of (s, 1H), 9.60 (br s, 1H), 8.94 (s, [(methylsulfonyl)amino]phenyl}- Compound 42 1H), 8.08 (d, J = 8.1 Hz, 1H), 2-oxo-8- 7.90 (d, J = 8.7 Hz, 1H), propyl-2H- 7.20 (d, J = 8.7 Hz, 1H), chromene-3- 7.08-7.04 (m, 2H), 3.94 (s, 3H), 2.93 (s, carboxamide 3H), 2.80-2.70 (m, 2H), 2.28 (s, 3H), 2.60-2.50 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 53 4-{[(7-methoxy- Compound 45 was (300 MHz, CDCl₃) δ 10.94 (s, 2-oxo-8-propyl- used in place of 1H), 8.94 (s, 1H), 8.40 (d, J = 9.3 Hz, 2H-chromen-3- Compound 42 1H), 7.58 (d, J = 8.7 Hz, yl)carbonyl]amino}- 1H), 7.18-7.15 (m, 2H), 6.98 (d, 3- J = 9.0 Hz, 1H), 3.98 (s, 3H), methylphenyl 3.14 (s, 3H), 2.86 (t, J = 7.5 Hz, methanesulfonate 2H), 2.45 (s, 3H), 1.66-1.59 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

EXAMPLE 12 Compound 50 N-[4-Hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide

Step 1: 4-amino-3-(trifluoromethyl)phenol [CAS 445-04-5] (0.292 g, 1.65 mmol), imidazole (0.280 g, 4.11 mmol), and tert-butylchlorodimethylsilane (0.36 g, 2.32 mmol) in DMF (5 mL) were stirred at room temperature overnight. After standard aqueous work up, the crude was purified by MPLC using (10% EtOAc/Hexanes) to give an orange oil.

Step 2: 4-((tert-butyldimethylsilyl)oxy)-2-(trifluoromethyl)aniline was substituted in the method used in Example 1.

Step 3: The compound from Step 2 (0.23 g, 0.430 mmol) in THF (5 mL) was treated with 1.0 M TBAF (0.480 mL, 0.480 mmol) solution in THF at 0° C. for 30 minutes. Solvent was removed and residue was purified by MPLC (40% EtOAc/Hexanes) to give the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 10.71 (s, 1H), 10.08 (s, 1H), 8.97 (s, 1H), 7.94-7.91 (m, 2H), 7.21 (d, J=8.7 Hz, 1H), 7.09-7.07 (m, 2H), 3.95 (s, 3H), 2.75-2.70 (m, 2H), 1.58-1.50 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

Example 13 Compound 55 7-Methoxy-N-{2-methyl-4-[(methylsulfonyl)methyl]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide

Step 1: 4-(Bromomethyl)-2-methyl-1-nitrobenzene [CAS 141281-38-1] (1.45 g, 6.11 mmol) was added as a solid to sodium methanethiolate (0.50 g, 6.78 mmol) in DMF at 0° C. The reaction mixture was slowly warmed to room temperature overnight. After aqueous work up, crude was purified by MPLC (7.5% EtOAc/Hexanes) to give an oil which was used in the next step.

Step 2: To methyl(3-methyl-4-nitrobenzyl)sulfane (0.840 g, 4.26 mmol) in CH₂Cl₂ (15 mL) was added m-CPBA (3.0 eq) at room temperature for 2 hours. After aqueous work up, crude was purified by MPLC (60% EtOAc/Hexanes) which was used in the next step.

Step 3: The previous compound from step 2, was hydrogenated at 50 psi with 10% Pd/C (0.084 g) in MeOH/THF (30 mL) for 3.5 hours. The reaction mixture was filtered and purified by MPLC (1% MeOH/CH₂Cl₂) to give 2-methyl-4((methylsulfonyl) methyl) aniline as a light orange solid.

Step 4: 2-methyl-4-((methylsulfonyl)methyl)aniline was substituted in the method used in Example 1.

¹H NMR (300 MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.98 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 7.93 (d, J=9.3 Hz, 1H), 7.29-7.21 (m, 3H), 4.41 (s, 2H), 3.95 (s, 3H), 2.89 (s, 3H), 2.80-2.71 (m, 2H), 2.34 (s, 3H), 1.60-1.50 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 14 Compound 66 N-[4-(Aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide

To a solution of Intermediate 1 (0.10 g, 0.381 mmol) in CH₂Cl₂ (5.0 mL) was added diisopropyl ethyl amine (0.1 mL, 0.572 mmol) and a 50% solution of propylphosphonic anhydride in ethyl acetate (0.340 mL, 0.572 mmol). The mixture was stirred for 30 minutes at room temperature. 4-Amino-3-methylbenzenesulfonamide [CAS # 53297-70-4] (0.071 g, 0.381 mmol) was added to the reaction mixture at room temperature and stirred overnight. The reaction mixture was then poured onto ice water (25 mL) and CH₂Cl₂ (25 mL) added. The organic layer was separated and washed with brine (25 mL), dried with Na₂SO₄, filtered and concentrated to dryness. The residue was triturated with CH₂Cl₂/Hexanes and then the solid was purified with a MPLC to give the title compound as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.03 (s, 1H), 8.46 (d, J=8.5 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.79-7.65 (m, 2H), 7.33-7.18 (m, 3H), 3.98 (s, 3H), 2.81-2.71 (m, 2H), 2.43 (s, 3H), 1.64-1.50 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

EXAMPLE 15 Compound 67 3-{[(4-{[(7-Methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)sulfonyl]amino}propanoic acid

Step 1: To a solution of 7-methoxy-N-(2-methylphenyI)-2-oxo-8-propyl-2H-chromene-3-carboxamide prepared following the procedure in WO2009019167 (0.104 g, 0.296 mmol) in CH₂Cl₂ (5.0 mL) was added chlorosulfonic acid (0.196 mL, 2.96 mmol) in CH₂Cl₂ (1.5 mL) dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and carefully quenched with ice water (25 mL) and diluted with CH₂Cl₂ (25 mL). The organic layer is separated and washed with brine (25 mL), dried with Na₂SO₄, filtered and concentrated to dryness. The yellow solid, 4-(7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamido)-3-methylbenzene-1-sulfonyl chloride was used as such in the next steps.

Step 2: To a solution of 4-(7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamido)-3-methylbenzene-1-sulfonyl chloride (0.054 g, 0.122 mmol) in THF (7.0 mL) was added tert-butyl-3-aminopropanoate hydrochloride (0.028 g, 0.152 mmol) and diisopropylethylamine (0.086 mL, 0.500 mmol). After stirring at room temperature over night the solvent was concentrated to dryness and re-dissolved in CH₂Cl₂ and washed with water. The organic layer was separated and dried with Na₂SO₄, filtered and concentrated to dryness to give a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.02 (s, 1H), 8.50 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.69 (br s, 2H), 7.65 (s, 1H), 7.24 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 2.87-2.96 (m, 2H), 2.79-2.70 (m, 2H), 2.42 (s, 3H), 2.33 (t, J=7.3 Hz, 2H), 1.60-1.48 (m, 2H), 1.37 (s, 9H), 0.92 (t, J=7.3 Hz, 3H).

Step 3: The solid was dissolved in CH₂Cl₂ (4.5 mL) and treated with TFA (0.5 mL). After stirring at room temperature for 5 hours the solvent was concentrated to dryness to give the title compound as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 10.91 (s, 1H), 8.96 (s, 1H), 8.44 (d, J=8.2 Hz, 1H), 7.91 (d, J=10.0 Hz, 1H), 7.64 (br s, 1H), 7.60 (s, 1H), 7.50 (t, J=6.0 Hz, 1H), 7.18 (d, J=10.0 Hz, 1H), 3.91 (s, 3H), 2.92-2.82 (m, 2H), 2.64-2.73 (m, 2H), 2.37 (s, 4H), 2.34-2.20 (m, 3H), 1.57-1.43 (m, 2H), 0.87 (t, J=7.5 Hz, 3H).

EXAMPLE 16 Compound 68 7-Methoxy-N-{2-methyl-4-[(methylamino)sulfonyl]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide

Compound 68 was prepared by substituting methylamine in Step 2 in the method of Example 15 for Compound 67.

¹H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.01 (s, 1H), 8.50 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.64 (s, 1H), 7.32 (d, J=4.7 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 3.96 (s, 3H), 2.74 (t, J=7.0 Hz, 2H), 2.42 (s, 3H), 1.62-1.49 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

EXAMPLE 17 GTP γ³⁵S Binding Assay

The S1P1 activity of the compounds according to the invention, were tested using the GTP γ³⁵S binding assay. The compounds were assessed for their ability to activate or block activation of the human S1P1 receptor in cells stably expressing the S1P1 receptor. Some of the results are presented in Table 3.

GTP γ³⁵S binding was measured in the medium containing (mM) HEPES 25, pH 7.4, MgCl₂ 10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP γ³⁵S, and 5 μg membrane protein in a volume of 150 μl. Test compounds were included in the concentration range from 0.08 to 5,000 nM unless indicated otherwise. Membranes were incubated with 100 μM 5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDP for 10 min on ice. Drug solutions and membrane were mixed, and then reactions were initiated by adding GTP γ³⁵S and continued for 30 min at 25° C. Reaction mixtures were filtered over Whatman GF/B filters under vacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25, pH7.4, MgCl₂ 10 and NaCl 100). Filters were dried and mixed with scintillant, and counted for ³⁵S activity using a β-counter. Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in the absence of agonist. Binding data were analyzed using a non-linear regression method. In case of antagonist assay, the reaction mixture contained 10 nM S1P in the presence of test antagonist at concentrations ranging from 0.08 to 5000 nM.

Activity potency: S1P1 receptor from GTP γ³⁵S:nM, (EC₅₀),

TABLE 3 Compound EC₅₀ number IUPAC name (nM) 6 N-(3-bromopyridin-4-yl)-7-methoxy-2-oxo-8- 19.0 propyl-2H-chromene-3-carboxamide 5 N-(2-bromophenyl)-7-methoxy-2-oxo-8-propyl-2H- 26.4 chromene-3-carboxamide 62 (4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl- 3.1 2H-chromen-3-yl)carbonyl]amino}-3- methylphenyl)amino]-5-oxopentanoic acid 38 N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2- 3.5 oxo-8-propyl-2H-chromene-3-carboxamide 49 N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy- 14.3 2-oxo-8-propyl-2H-chromene-3-carboxamide

EXAMPLE 18 Lymphopenia Assay in Mice

Test drugs are prepared in a solution containing 3% (w/v) 2-hydroxy propyl β-cyclodextrin (HPBCD) and 1% DMSO to a final concentration of 1 mg/ml, and subcutaneously injected to female C57BL6 mice (CHARLES RIVERS) weighing 20-25 g at the dose of 10 mg/Kg. Blood samples are obtained by puncturing the submandibular skin with a Goldenrod animal lancet at 5, 24, 48, 72, and 96 hrs post drug application. Blood is collected into microvettes (SARSTEDT) containing EDTA tripotassium salt. Lymphocytes in blood samples are counted using a HEMAVET Multispecies Hematology System, HEMAVET HV950FS (Drew Scientific Inc.).

(Hale, J. et al Bioorg. & Med. Chem. Lett. 14 (2004) 3351). 

1. A compound having Formula I, its enantiomers, diastereoisomers, hydrates, solvates, crystal forms and individual isomers, tautomers or a pharmaceutically acceptable salt thereof,

wherein: R¹ is hydrogen, halogen or C₁₋₆alkyl; R² is CR³ or N; R³ is hydrogen, halogen, O(C₁₋₆alkyl), S(C₁₋₆alkyl), cyano, aldehyde, heterocycle, C₁₋₆alkyl or hydroxyl; R⁴ is CR⁵ or N; R⁵is hydrogen, halogen, hydroxyl or non-substituted C₁₋₆alkyl; R⁶is CR⁷ or N; R⁷is —NHR¹², —S(O)₂R¹⁴, —C(O)NHR¹⁶, —OR¹⁷, hydrogen, halogen, phosphonic acid, boronic acid, —CH₂—OH, —CH₂—S(O)₂CH₃, —(CH₂)_(a)—NH—(CH₂)_(b)—O_(c)—P(O)(OH)₂, —(CH₂)_(d)—C(NH₂)(CH₂OH)(CH₂—O—-P(O)(OH)₂), —(CH₂)_(e)—C(NH₂)(CH₃)(CH₂—O—P(O)(OH)₂); or —(CH₂)_(f)—NH—(CH₂)_(g)—SO₃H; a is 1 or 2; b is 2 or 3; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0 or 1; g is 2 or 3; R⁸ is CR⁹ or N; R⁹ is hydrogen, halogen, non-substituted C₁₋₆alkyl or hydroxyl; R¹⁰ is CR¹¹ or N; R¹¹ is hydrogen, halogen or C₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, —C(O)R¹³, —S(O)₂(C₁₋₃alkyl) or heterocycle; R¹³ is amino or C₁₋₆alkyl; R¹⁴ is C₁₋₄alkyl, NHR¹⁵ or hydroxyl; R¹⁵ is hydrogen or C₁₋₆alkyl; R¹⁶ is hydrogen or C₁₋₆alkyl; R¹⁷ is hydrogen, C₁₋₆alkyl or —S(O)₂(C₁₋₃alkyl); R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl; R¹⁹ is hydrogen, halogen or C₁₋₆alkyl; R²⁰ is hydrogen, halogen or C₁₋₆alkyl; and R²¹ is —OC₁₋₄alkyl.
 2. A compound according to claim 1, wherein R¹ is hydrogen; and R² is CR³; and R³ is halogen, O(C₁₋₆alkyl), S(C₁₋₆alkyl), cyano, aldehyde, heterocycle, C₁₋₆alkyl; and R⁴ is CR⁵ or N; and R⁵ is hydrogen or halogen; and R⁶ is CR⁷ or N; and R⁷ is —NHR¹², —S(O)₂R¹⁴, —OR¹⁷, hydrogen, phosphonic acid, boronic acid, —CH₂—OH, —CH₂—S(O)₂CH₃; and R⁸ is CR⁹ or N; and R⁹ is hydrogen, halogen or non-substituted C₁₋₆alkyl; and R¹⁰ is CR¹¹; and R¹¹ is hydrogen, halogen or C₁₋₆alkyl; and R¹² is —S(O)₂(C₁₋₃alkyl), C(O)R¹³ or heterocycle; and R¹³ is C₁₋₆alkyl; and R¹⁴ is NHR¹⁵; and R¹⁵ is hydrogen or C₁₋₆alkyl; and R¹⁶ is C₁₋₆alkyl; and R¹⁷ is hydrogen, or —S(O)₂(C₁₋₃alkyl); and R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl; and R¹⁹ is hydrogen; and R²⁰ is hydrogen; and R²¹ is —OC₁₋₄alkyl.
 3. A compound according to claim 1, wherein R¹ is hydrogen; and R² is CR³; and R³ is halogen, O(C₁₋₆alkyl), C₁₋₆alkyl; and R⁴ is CR⁵ or N; and R⁵ is hydrogen; and R⁶ is CR⁷ or N; and R⁷ is —NHR¹², —S(O)₂R¹⁴, —OR¹⁷, hydrogen, phosphonic acid or boronic acid; and R⁸ is CR⁹; and R⁹ is hydrogen; and R¹⁰ is CR¹¹; and R¹¹ is hydrogen or C₁₋₆alkyl; and R¹² is —S(O)₂(C₁₋₃alkyl) or C(O)R¹³; and R¹³ is C₁₋₆alkyl; and R¹⁴ is NHR¹⁵; and R¹⁵ is hydrogen; and R¹⁷ is hydrogen; and R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl; and R¹⁹ is hydrogen; and R²⁰ is hydrogen; and R²¹ is —OC₁₋₄alkyl.
 4. A compound according to claim 1 selected from: N-[4-(hydroxymethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(4-amino-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 3-{[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)sulfonyl]amino}propanoic acid; N-(2-chlorophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-N-[4-(piperidin-3-ylamino)phenyl]-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[4-(pyrrolidin-3-ylamino)phenyl]-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-N-{4-[(piperidin-2-ylmethyl)amino]phenyl}-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-N-{4-[(piperidin-3-ylmethyl)amino]phenyl}-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methylphenyl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-cyanophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-4-[(methylamino)sulfonyl]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-[2-(methylthio)phenyl]-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethoxy)phenyl]-2H-chromene-3-carboxamide; N-[2-(2-furyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(3-fluoro-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-fluorophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-ethylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methoxyphenyl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide; N-(2-bromophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl methanesulfonate; N-[2-(difluoromethoxy)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(3-bromopyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(3-chloropyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-chloro-5-methylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-(2-propylphenyl)-2H-chromene-3-carboxamide; N-(6-amino-2-methylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-pyridin-4-yl-2H-chromene-3-carboxamide; 7-methoxy-N-(3-methylpyridin-4-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[3-(trifluoromethyl)pyridin-4-yl]-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-pyridin-3-yl-2H-chromene-3-carboxamide; N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; 7-methoxy-N-(3-methylpyridin-2-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-formylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(3-chloropyridazin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (3-chloro-4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}phenyl)boronic acid; N-(2-chloro-5-fluoropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)phosphonic acid; N-[4-(aminosulfonyl)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid; 8-isopropoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; 8-isopropoxy-7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-2H-chromene-3-carboxamide; 8-ethoxy-7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-2H-chromene-3-carboxamide; 8-ethoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; 8-ethoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide; 8-isopropoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-4-[(methylsulfonyl)methyl]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-{2-chloro-4-[(methylsulfonyl)amino]phenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid; N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-8-ethoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-8-isopropoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide; 7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-8-ethyl-7-methoxy-2-oxo-2H-chromene-3-carboxamide.
 5. A compound according to claim 1 selected from: 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide; N-(3-bromopyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-bromophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[3-(trifluoromethyl)pyridin-4-yl]-2H-chromene-3-carboxamide; N-(3-chloropyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 8-ethoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; N-(2-ethylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)phosphonic acid; (3-chloro-4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}phenyl)boronic acid; 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethoxy)phenyl]-2H-chromene-3-carboxamide; N-[2-(difluoromethoxy)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-8-isopropoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-8-ethoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid; N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid; N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide.
 6. A compound according to claim 1 selected from: 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid; N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid; N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide.
 7. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluents or carrier.
 8. A pharmaceutical composition according to claim 7 wherein the compound is selected from 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)phenyl]-2H-chromene-3-carboxamide; N-(3-bromopyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-bromophenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[3-(trifluoromethyl)pyridin-4-yl]-2H-chromene-3-carboxamide; N-(3-chloropyridin-4-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 8-ethoxy-7-methoxy-2-oxo-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; N-(2-ethylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)phosphonic acid; (3-chloro-4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}phenyl)boronic acid; 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethoxy)phenyl]-2H-chromene-3-carboxamide; N-[2-(difluoromethoxy)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-8-isopropoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-8-ethoxy-7-methoxy-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid; N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid; N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide.
 9. A pharmaceutical composition according to claim 7 wherein the compound is selected from 7-methoxy-2-oxo-8-propyl-N-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromene-3-carboxamide; N-(2-bromopyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(2-ethylpyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methylpyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7,8-diethoxy-N-{4-[(methylsulfonyl)amino]-2-(trifluoromethyl)phenyl}-2-oxo-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-bromophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-chlorophenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methyl-6-[(methylsulfonyl)amino]pyridin-3-yl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; 7-methoxy-N-{2-methoxy-4-[(methylsulfonyl)amino]phenyl}-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(aminosulfonyl)-2-methylphenyl]-7,8-diethoxy-2-oxo-2H-chromene-3-carboxamide; 7-methoxy-N-(2-methoxypyridin-3-yl)-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-{4-[(ethylsulfonyl)amino]-2-methylphenyl}7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-(4-hydroxy-2-methylphenyl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (3S)-3-amino-4-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-4-oxobutanoic acid; N-(2-chloropyridin-3-yl)-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; (4R)-4-amino-5-[(4-{[(7-methoxy-2-oxo-8-propyl-2H-chromen-3-yl)carbonyl]amino}-3-methylphenyl)amino]-5-oxopentanoic acid; N-[4-(aminosulfonyl)-2-methylphenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide; N-[4-hydroxy-2-(trifluoromethyl)phenyl]-7-methoxy-2-oxo-8-propyl-2H-chromene-3-carboxamide.
 10. A method of treating a disorder associated with sphingosine-1-phosphate 1 (S1P1) receptor modulation, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I

wherein: R¹ is hydrogen, halogen or C₁₋₆alkyl; R² is CR³ or N; R³ is hydrogen, halogen, O(C₁₋₆alkyl), S(C₁₋₆alkyl), cyano, aldehyde, heterocycle, C₁₋₆alkyl or hydroxyl; R⁴ is CR⁵ or N; R⁵is hydrogen, halogen, hydroxyl or non-substituted C₁₋₆alkyl; R⁶is CR⁷ or N; R⁷is —NHR¹², —S(O)₂R¹⁴, —C(O)NHR¹⁶, —OR¹⁷, hydrogen, halogen, phosphonic acid, boronic acid, —CH₂—OH, —CH₂—S(O)₂CH₃, —(CH₂)_(a), —NH—(CH₂)_(b)—O_(c)—P(O)(OH)₂, —(CH₂)_(d)—C(NH₂)(CH₂OH)(CH₂—O—P(O)(OH)₂), —(CH₂)_(e)—C(NH₂)(CH₃)(CH₂—O—P(O)(OH)₂); or —(CH₂)_(f)—NH—(CH₂)_(g)—SO₃H; a is 1 or 2; b is 2 or 3; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0 or 1; g is 2 or 3; R⁸ is CR⁹ or N; R⁹ is hydrogen, halogen, non-substituted C₁₋₆alkyl or hydroxyl; R¹⁰ is CR¹¹ or N; R¹¹ is hydrogen, halogen or C₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, —C(O)R¹³, —S(O)₂(C₁₋₃alkyl) or heterocycle; R¹³ is amino or C₁₋₆alkyl; R¹⁴ is C₁₋₄alkyl, NHR¹⁵ or hydroxyl; R¹⁵ is hydrogen or C₁₋₆alkyl; R¹⁶ is hydrogen or C₁₋₆alkyl; R¹⁷ is hydrogen, C₁₋₆alkyl or —S(O)₂(C₁₋₃alkyl); R¹⁸ is C₂₋₄alkyl or —OC₂₋₄alkyl; R¹⁹ is hydrogen, halogen or C₁₋₆alkyl; R²⁰ is hydrogen, halogen or C₁₋₆alkyl; and R²¹ is —OC₁₋₄alkyl.
 11. A method of claim 10, wherein the pharmaceutical composition is administered to the mammal to treat ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases, various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression, rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, autoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases, urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection, ischemia reperfusion injury and atherosclerosis; or wound healing, scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains. 